Metastable crystal modification and method for producing the same (I)
11512047 · 2022-11-29
Assignee
Inventors
Cpc classification
C07C279/14
CHEMISTRY; METALLURGY
C07C279/14
CHEMISTRY; METALLURGY
International classification
Abstract
The present invention relates to a new crystal modification of N-(aminoiminomethyl)-2-aminoacetic acid as well as a method for producing this crystal modification.
Claims
1. A thermodynamically metastable crystal form of N-(aminoiminomethyl)-2-aminoacetic acid, wherein the crystal form in the x-ray powder diffractogram of the crystal form shows the strongest reflex bands at 2Θ=20.2°, 23.3°, 23.8° and 25.3° at a measuring accuracy of +/−0.2° when using Cu-Kα.sub.1 radiation.
2. The crystal form according to claim 1, wherein the crystal form has the orthorhombic space group P2.sub.12.sub.12.sub.1 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. The crystal form according to claim 2, wherein the crystal form has a cell volume of 1052 Å.sup.3 at 105 Kelvin.
4. The crystal form according to claim 1, wherein the crystal form has an experimental crystal density of 1.41 g/cm.sup.3+/−0.03 g/cm.sup.3 at 20° C.
5. The crystal form according to claim 1, wherein the crystal form has an endothermic melt heat within a range of 850 to 870 J/g.
6. The crystal form according to claim 1, wherein the crystal form has a decomposition point within a range of 270 to 275° C.
7. A method for producing a thermodynamically metastable crystal form of N-(aminoiminomethyl)-2-aminoacetic acid according to claim 1, wherein N-(aminoiminomethyl)-2-aminoacetic acid is crystallized from a solution containing 5 to 50 wt. % calcium chloride.
8. The method according to claim 7, wherein N-(aminoiminomethyl)-2-aminoacetic acid is crystallized from a solution containing 10 to 40 wt. % calcium chloride.
9. The method according to claim 7, wherein N-(aminoiminomethyl)-2-aminoacetic acid is crystallized within a temperature range of −40 to 100° C.
10. The method according to claim 7, wherein N-(aminoiminomethyl)-2-aminoacetic acid is crystallized with a cooling rate within a range of 0.01 to 5 K/min within a temperature range of −40 to 100° C.
11. The method according to claim 7, wherein the solution contains a solvent from the group of water, alcohols, esters, nitriles, ketones or mixture of the same as a solvent.
12. An animal feed additive comprising a thermodynamically metastable crystal form of claim 1.
Description
(1) The Drawings Show:
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EXAMPLES
(10) X-Ray Powder-Diffractometric Measurement
(11) Within the scope of the present examples x-ray powder-diffractometric measurements were carried out using a powder diffractometer Bruker D2 Phaser with theta/2theta geometry, a LYNXEYE detector, Cu-Kα.sub.1 radiation with the wavelength 1.5406 Å with an acceleration voltage of 30 kV and an anode current of 10 mA, a nickel filter and a increment of 0.02°. The samples provided for investigation were ground in an agate mortar pressed onto the sample plate according to manufacturer's instructions, and the surface smoothed.
(12) Single Crystal x-Ray Structure Analysis
(13) A suitable crystal was produced through evaporating an aqueous solution of N-(aminoiminomethyl)-2-aminoacetic acid in the presence of calcium chloride. The single crystal measurement was carried out at 105 Kelvin on a crystal with the dimensions 0.02*0.02*0.09 mm, using monochromatic Mo-Kα (molybdenum-K-alpha) radiation with the wavelength 0.71073 Å, using a dual-circuit diffractometer Bruker D8 Venture TXS. The refinement of the x-ray crystal data using 2072 independent reflexes was carried out with the method of the smallest error squares up to an R value (F.sub.obs) of 0.0381. The Position of the NH- and OH-hydrogen atoms was refined, which fixes the CH-hydrogen atoms in the calculated position. The result of the x-ray single crystal structure analysis is demonstrated in
Example 1 (Comparison)—Recrystallisation of N-(Aminoiminomethyl)-2-Aminoacetic Acid from Water
(14) 400 g water was provided at 80° C. and a total of 11.66 g N-(aminoiminomethyl)-2-aminoacetic acid with a content of 99.0%, here in crystal form A, dissolved in the same spoon by spoon, wherein the solubility limit was exceeded with the last portion. This was filtered at 80° C., a further 100 g water was added to the filtrate and heated to 80° C. A barely saturated clear solution was formed. Slow cooling to 20° C. over 4 hours crystallised N-(aminoiminomethyl)-2-aminoacetic acid. The precipitated crystals were filtered out and dried in a vacuum at 60° C. 6.51 g of N-(aminoiminomethyl)-2-aminoacetic acid with a content of 99.1% was obtained.
(15) The obtained product is present in the form of fine needle-shaped crystals. The fine needle-shaped crystals were microscopically examined (see
Example 2 (According to the Invention)—Recrystallisation of N-(Aminoiminomethyl)-2-Aminoacetic Acid from a 30% Calcium Chloride Solution
(16) A 30% solution was produced from 150 g water-free calcium chloride and 350 g water. N-(aminoiminomethyl)-2-aminoacetic acid of the same composition as in example 1 (i.e. 99.0% content, crystal form A) was added spoon by spoon to 400 g of this solution at 80° C. Only at an added quantity of 74.28 g was the solubility limit exceeded. The low solids content was filtered out at 80° C., not washed, the filtrate admixed with the remaining 100 g of the 30% solution of calcium chloride, and stirred at 80° C. for 1 hour. A clear, colourless solution was obtained. Slow cooling to 20° C. over 4 hours crystallised N-(aminoiminomethyl)-2-aminoacetic acid. The precipitated crystal aggregates were filtered out, washed 3 times with water at 20° C. and dried at 60° C. 46.42 g N-(aminoiminomethyl)-2-aminoacetic acid with a content of 99.2% was obtained. The obtained quantity is therefore 7 times greater than in example 1, which is due to the solubility of N-(aminoiminomethyl)-2-aminoacetic acid that is strongly increased through calcium chloride.
(17) An analogously recorded powder diffractogram (see
Example 3 (According to the Invention)—Recrystallisation of N-(Aminoiminomethyl)-2-Aminoacetic Acid from a 15% Calcium Chloride Solution
(18) Example 2 was repeated analogously with 500 g of a 15% calcium chloride solution produced from 75 g water-free calcium chloride and 425 g water. The saturation limit was reached with 42.7 g N-(aminoiminomethyl)-2-aminoacetic acid in 400 g of this solvent mixture at 80° C. Following addition of the remaining 100 g of solvent, crystallisation of the initially clear solution, filtration, washing and drying, 27.2 g N-(aminoiminomethyl)-2-aminoacetic acid with a content of 99.2% was obtained.
(19) The powder diffractogram of the spherical crystal aggregates indicated the sole presence of form B. The spherical, radially radiating aggregates were microscopically examined (see
Example 3a (According to the Invention)—Recrystallisation of N-(Aminoiminomethyl)-2-Aminoacetic Acid from a 10% Calcium Chloride Solution
(20) Example 2 was repeated analogously with 500 g of a 10% calcium chloride solution produced from 50 g water-free calcium chloride and 450 g water. The saturation limit was reached with 29.4 g N-(aminoiminomethyl)-2-aminoacetic acid in 400 g of this solvent mixture at 80° C. Following addition of the remaining 100 g of solvent, crystallisation of the initially clear solution, filtration, washing and drying, 23.5 g N-(aminoiminomethyl)-2-aminoacetic acid with a content of 99.3% was obtained.
(21) The powder diffractogram indicated the presence of a mixture of crystal form A and crystal form B. The ration of both polymorphs was approx. 1:1.
Example 3b (Comparison)—Recrystallisation of N-(Aminoiminomethyl)-2-Aminoacetic Acid from a 1% Calcium Chloride Solution
(22) Example 2 was repeated analogously with 500 g of a 1% calcium chloride solution produced from 5 g water-free calcium chloride and 495 g water. The saturation limit was reached with 13.4 g N-(aminoiminomethyl)-2-aminoacetic acid in 400 g of this solvent mixture at 80° C. Following addition of the remaining 100 g of solvent, crystallisation of the initially clear solution, filtration, washing and drying, 11.0 g N-(aminoiminomethyl)-2-aminoacetic acid with a content of 99.4% was obtained.
(23) The powder diffractogram of the fine needle-shaped crystal aggregates indicated the sole presence of form A.
(24) Depending on the calcium chloride concentration the creation of form A or form B can therefore be influenced. The solubility (i.e. saturation limit) of N-(aminoiminomethyl)-2-aminoacetic acid increases strongly with the calcium chloride concentration.
Example 4 (Comparison)—Recrystallisation of N-(Aminoiminomethyl)-2-Aminoacetic Acid from a 50% Solution of Magnesium Chloride Hexahydrate
(25) Example 2 was repeated analogously with 500 g of a solution produced from 250 g magnesium chloride hexahydrate and 250 g water. The saturation limit was reached with 76.6 g N-(aminoiminomethyl)-2-aminoacetic acid in 400 g of this solvent mixture at 80° C. Following addition of the remaining 100 g of solvent, crystallisation, filtration, washing and drying, 49.1 g N-(aminoiminomethyl)-2-aminoacetic acid with a content of 99.1% was obtained.
(26) The powder diffractogram of the fine needle-shaped crystal aggregates obtained indicated the sole presence of form A. MgCl.sub.2, which is very similar to CaCl.sub.2, thus does not affect the crystallisation of N-(aminoiminomethyl)-2-aminoacetic acid in form B even though the solubility of N-(aminoiminomethyl)-2-aminoacetic acid is strongly increased in a similar way by the presence of the salt.
Example 5 (Comparison)—Synthesis of N-(Aminoiminomethyl)-2-Aminoacetic Acid from Glycine and Cyanamide in Aqueous Solution
(27) 112.6 g (1.5 mol) glycine was dissolved in 300 g water. The solution was admixed with 21.6 g (0.27 mol) of 50% caustic soda, wherein a pH value of 8.4 resulted. At 80° C. over a period of 4 hours a solution of 42.04 g (1.0 mol) cyanamide dissolved in 42 g water was added. The post-reaction took place for a further hour at 80° C. The obtained suspension was cooled to 20° C., filtered, 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%.
(28) A powder diffractogram of the obtained fine needle-shaped crystals indicated the sole presence of form A.
Example 6 (According to the Invention)—Synthesis of N-(Aminoiminomethyl)-2-Aminoacetic Acid from Glycine and Cyanamide in a 33% Calcium Chloride Solution
(29) A solution was produced from 100 g water-free calcium chloride and 200 g water. 112.6 g (1.5 mol) glycine was dissolved in this and a pH value of 8.4 set with 21.6 g (0.27 mol) of 50% caustic soda. At 80° C. over a period of 4 hours a solution of 42.04 g (1.0 mol) cyanamide dissolved in 42 g water was added. The post-reaction took place for a further hour at 80° C. The obtained suspension was cooled to 20° C., filtered, washed with water and dried at 60° C. 99.3 g N-(aminoiminomethyl)-2-aminoacetic acid with a content of 99.2% was obtained. The yield was 84.8%.
(30) A powder diffractogram of the obtained rounded crystal aggregates of radially radiating individual crystals indicated the sole presence of form B.
Example 6a (According to the Invention)—Synthesis of N-(Aminoiminomethyl)-2-Aminoacetic Acid from Glycine and Cyanamide in a 15% Calcium Chloride Solution
(31) A solution was produced from 45 g water-free calcium chloride and 255 g water. 112.6 g (1.5 mol) glycine was dissolved in this and a pH value of 8.4 set with 21.5 g (0.27 mol) of 50% caustic soda. At 80° C. over a period of 4 hours a solution of 42.04 g (1.0 mol) cyanamide dissolved in 42 g water was added. The post-reaction took place for a further hour at 80° C. The obtained suspension was cooled to 20° C., filtered, washed with water and dried at 60° C. 99.6 g N-(aminoiminomethyl)-2-aminoacetic acid with a content of 99.3% was obtained. The yield was 84.5%.
(32) A powder diffractogram of the obtained crystals indicated that a mixture of form A and form B was present wherein form B represented by far the largest proportion.
Example 6b (Comparison)—Synthesis of N-(Aminoiminomethyl)-2-Aminoacetic Acid from Glycine and Cyanamide in a 1% Calcium Chloride Solution
(33) A solution was produced from 3 g water-free calcium chloride and 297 g water. 112.6 g (1.5 mol) glycine was dissolved in this and a pH value of 8.4 set with 21.4 g (0.27 mol) of 50% caustic soda. At 80° C. over a period of 4 hours a solution of 42.04 g (1.0 mol) cyanamide dissolved in 42 g water was added. The post-reaction took place for a further hour at 80° C. The obtained suspension was cooled to 20° C., filtered, washed with water and dried at 60° C. 100.1 g N-(aminoiminomethyl)-2-aminoacetic acid with a content of 99.2% was obtained. The yield was 84.8%.
(34) A powder diffractogram of the obtained crystals indicated that only form A was present.
(35) Even if N-(aminoiminomethyl)-2-aminoacetic acid is generated through reaction between glycine and cyanamide, the resulting crystal form can be controlled through the presence of different concentration of calcium chloride.
Example 7—Physical Chemical Characterisation N-(Aminoiminomethyl)-2-Aminoacetic Acid of Form A and Form B
(36) 7.1 Melting or Decomposition Point
(37) A Mettler DSC 3+ unit with a 40 μl aluminium pan was used for Dynamic Differential Scanning Calorimetry (DSC). The heating rate was 10 Kelvin per minute within a temperature range of 30 to 350° C. Approx. 1.4 mg each of the products from example 1 and 2 was weighed into the aluminium pan and measured at atmospheric pressure (960 mbar at a height position of 500 m over NN).
(38) The sample from example 1 (═N-(aminoiminomethyl)-2-aminoacetic acid of the form A) showed an onset (turning point of the melting graph projected onto the base line) of 280.5° C. and a peak temperature of the melting graph of 286.3° C. The total endothermic melt heat was 887 J/g. The product discoloured during melting from white to brown.
(39) The sample from example 2 (═N-(aminoiminomethyl)-2-aminoacetic acid form B) was analogously measured. It showed an onset of 272.5° C. and a peak of 280.4° C., the melt heat was 860 J/g, the discolouration was identical.
(40) Form B therefore melts at approx. 6 to 8 Kelvin lower than form A and has a 27 J/g lower melt heat or a 27 J/g higher lattice energy, respectively. In other words, 27 J/g less energy is required for form B than is needed for form A to reach an identical energy melt condition. Form B thus constitutes a metastable crystal form or an energetically higher positioned polymorph of N-(aminoiminomethyl)-2-aminoacetic acid under normal pressure and temperature conditions.
(41) 7.2 Determination of Water Solubility
(42) 100 g water of 5° C. was provided. The product from example 1 (═N-(aminoiminomethyl)-2-aminoacetic acid form A) was dissolved therein up to saturation, and the dissolved quantity determined through back weighing. The temperature was then increased to 20° C. and as much as required of the sample was added to reach saturation point. The same was repeated at further temperatures with a maximum at 95° C. An analogue measurement was carried out with the product from example 2 (═N-(aminoiminomethyl)-2-aminoacetic acid form B). The obtained solubility data for both products are graphically summarised in
(43) Both crystal forms of N-(aminoiminomethyl)-2-aminoacetic acid dissolve better in water as the temperature increases. The N-(aminoiminomethyl)-2-aminoacetic acid form B according to the invention dissolves by around 20% better than the known form A at any temperature.
(44) 7.3 Determination of Density
(45) Crystals of N-(aminoiminomethyl)-2-aminoacetic acid form A from example 1 were introduced to tetrachloromethane at 20° C., where they floated on the surface. A drop-by-drop addition of dichloromethane lowered the density of the liquid medium 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 pyknometer. 1.50 g/cm.sup.3 was measured.
(46) Crystals of the form B from example 2 were treated in the same way. The density at 20° C. was determined as 1.41 g/cm.sup.3.
(47) Form B therefore has 6% less density than form A. This correlates with the above mentioned lower lattice energy of form B. The measured crystal densities also agree with the x-ray crystal data calculated from the respective lattice constants.
(48) 7.4 Determination of Dust Content
(49) The product from example 1 was sieved through a sieve with a mesh width of 63 μm (equals a 230 mesh—mesh size). A 46 wt. % fine content was obtained. The sample from example 2 consisting of polygonal, rounded crystal aggregates, was treated in the same way. A fine content of below 3 wt. % was determined here. Low-dust, and thus safe-to-handle materials should have a dust content (i.e. grain content <63 μm) of below 10%. The product from example 2 (N-(aminoiminomethyl)-2-aminoacetic acid of the crystal form B) fulfils this, whilst comparison example 1 (N-(aminoiminomethyl)-2-aminoacetic acid of the crystal form A) does not fulfil it.
(50) 7.5 Determination of Angle of Repose
(51) The product from example 1, consisting of needle-shaped crystals matted to each other, was poured through a funnel onto a level surface with a device according to DIN ISO 4324. After removing the funnel the slope angle of the obtained cone was determined with an angle measuring means. It was approx. 45°. N-(aminoiminomethyl)-2-aminoacetic acid form A therefore displays poor flow characteristics. The grainy product from example 2 was measured in the same way. A slope angle of approx. 25° was obtained here. N-(aminoiminomethyl)-2-aminoacetic acid form B therefore displays excellent flow characteristics.
(52) 7.6 Determination of Bulk Density
(53) A weighed-in quantity of the product from example 1 was placed in a measuring cylinder and partially compacted by firmly tapping the same on the laboratory table twice. The bulk density was determined as 0.37 g/cm.sup.3 from the filling height of the measuring cylinder. The product from example 2 was treated in the same way. A bulk density of 0.62 g/cm.sup.3 was determined here. N-(aminoiminomethyl)-2-aminoacetic acid of the form B therefore has a clearly increased bulk density, which is of advantage for the packing, transport and handling of the product.
(54) 7.7 Thermal Stability of N-(Aminoiminomethyl)-2-Aminoacetic Acid Form B a) N-(aminoiminomethyl)-2-aminoacetic 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 means of x-ray powder diffractometry. It remained unchanged in a pure crystal form B. b) N-(aminoiminomethyl)-2-aminoacetic acid form B from example 2 was moistened with 20% water, incubated in a closed vessel at 65° C. for 6 hours, then dried. The x-ray powder diffractogram showed no change, form B remained stable. c) N-(aminoiminomethyl)-2-aminoacetic acid form B from example 2 was turned into a 10% suspension in water. This suspension was stirred for 2 hours at 80° C. It was then cooled, the solids filtered out and dried. X-ray powder diffractometry showed that a mixture of crystal forms A and B was present. d) N-(aminoiminomethyl)-2-aminoacetic acid form B from example 2 was dissolved in water at 80° C., mostly crystallised once more through cooling the solution, filtered and dried. X-ray powder diffractometry resulted in a pure crystal form A.
(55) N-(aminoiminomethyl)-2-aminoacetic acid form B is thus very stable in solid form, but has the tendency to transfer into crystal form A via the aqueous solution. This characteristic also confirms the metastable crystal structure of form B.
Example 8—Synthesis of N-(Aminoiminomethyl)-2-Aminoacetic Acid According to Prior Art, in which Calcium is Present—DE 964 590 B
(56) Note: The calcium cyanamide used according to DE 964 590 B has a content of just 53%; this equals 15.9% N. In the following example calcium cyanamide with a content of 68.6% was used; this equals 24% N. The quantity used was adapted accordingly.
(57) 154.5 g technical calcium cyanamide with a content of 68.6% CaNCN was suspended in 800 g water. At 20° C. a mixture of 191.6 g of 96% sulphuric acid and 300 g water was added, wherein cyanamide was transformed into a solution and calcium sulfate precipitated from the solution and a pH value of 7.5 was obtained. Calcium sulfate and other insoluble components were filtered out and the filtrate set to a pH of pH 4.9 with a little sulphuric acid. The obtained solution was vaporised to a total volume of 200 cm.sup.3 under a reduced pressure of approx. 10 mbar. Further precipitated calcium sulfate was filtered out. The obtained aqueous cyanamide solution has a cyanamide content of 26.4% and a calcium content of 0.56 g/litre. (Note: equals a cyanamide yield of 95% and a gypsum solubility of 2.4 g/I).
(58) This cyanamide solution was admixed with 30 g glycine and set to a pH of 9.4 with 19.8 g of 50% aqueous caustic soda. The reaction mixture was heated to 95° C. for 1.5 hours and then cooled to room temperature overnight. Precipitated N-(aminoiminomethyl)-2-aminoacetic acid as well as any dicyandiamide also created was filtered out, the filter residue was taken in 180 g water, leached out at 50° C. for two hours, filtered at 50° C. and washed with water. After drying at 60° C., 38.4 g N-(aminoiminomethyl)-2-aminoacetic acid was obtained. The yield was 82% in relation to the glycine used.
(59) X-ray powder diffractometry showed that N-(aminoiminomethyl)-2-aminoacetic acid had been created only in crystal form A.