HK1083849B - Process for preparing hydrohalogen metal complexes of specific particle size - Google Patents

Description

The present invention relates to a process for the production of a granular hydrohalogenide salt of a particular metal complex compound composed of a divalent metal cation as the centre and an aminodicarbonic acid ion and, where appropriate, water as the ligand, by obtaining the hydrohalogenide salt with a specific particle size distribution.

Complexes of a divalent metal cation as a central ion and an aminodicarbonic acid ligand, as well as their hydrohalogenides and different methods for their production are known. Complexes of a divalent metal cation as a central ion and an aminodicarbonic acid ligand, such as magnesium L-aspartate, are largely easy to handle. In contrast, their hydrohalogenides, especially magnesium L-aspartate hydrochloride, are usually very hygroscopic, so their production is only possible at extremely low humidity.

To solve the problem of hygroscopicity of the hydrohalogenides described above, attempts have been made to produce a granular product with a reduced total surface area. However, all attempts to produce a granular product by spray drying have yielded an insufficient, usually very fine powder material which, due to the large surface area or the high proportion of very fine powder material, quickly assumes a honey-like consistency which makes it impossible to further process. For example, a very fine powder material is obtained under the spraying conditions specified in DE 32 38 118 A1 (see examples 1 to 5 of DE 32 118 A 381) (air temperature: about 180°C; air temperature: about 120°C).

Thus, the present invention is based on the technical task of producing hydrohalogenides from complex compounds composed of a bivalent metal cation as the centre and an amino-dicarbonic acid ion and, where appropriate, water as the ligand, which have good flow and solubility properties and reduced hygroscopicity.

This task is solved by providing the embodiments identified in the claims.

In particular, a method for the production of a granular hydrohalogenide of a complex compound consisting of a divalent metal cation as the centre and an amino-dicarbonic acid ion and, where appropriate, water as the ligand is provided, including the steps: (a) Presentation of the complex compound to the hydrochloric acid in aqueous solution. (b) Spray drying of the aqueous solution obtained in step (a) at an air inlet temperature of 300 to 350 °C and an air outlet temperature of 100 to 140 °C and a spray pressure of 3 to 5 bar.

The hydrohalogenides of the complex compounds produced in accordance with the invention can be prepared by various means, for example by mixing equimolar amounts of a metal salt of an amino-dicarbonic acid (with a divalent metal such as magnesium) and a corresponding metal halogenide in aqueous solution, but it is preferable to produce the hydrohalogenides of the complex compounds by converting an amino-dicarbonic acid with a hydroxide, oxide and/or carbonate of the metal (M) in aqueous solution and further converting the resulting aqueous solution or suspension with a metal halogenide (M) and/or halogenic acid in aqueous solution. The latter process can be made from more readily available starting materials and is more economical to carry out.

It is particularly preferable to mix an aqueous solution or suspension of 2 mol of the respective aminodicarbonic acid with an aqueous solution or suspension of 1 mol of the corresponding metal oxide, hydroxide and/or carbonate and an aqueous solution or suspension of 1 mol of the corresponding metal halide and stir until a clear solution is obtained. An equimolar amount of hydrogen halogen and a metal oxide, hydroxide and/or carbonate may also be used instead of the metal halide. The mixing is preferably carried out in a temperature range of 20 to about 90°C, or in the case of a slightly elevated exothermic reaction, until a clear solution is obtained by filtration. In cases where the solution or suspension contains metal halide, the solution or suspension may be purified first and then in the case of a slightly elevated temperature.

The hydrohalogenide of the complex compound is preferably a compound characterised by the following formula (I): Other where M2+ is a divalent metal cation, halogen, such as fluoride, chloride, bromide or iodide, n 1 or 2 and m 0 to 10, preferably 0, 1, 2 or 3.

The amino-dicarbon acids which can be used are not subject to any special restrictions in so far as they are capable of forming a chelate with a bivalent metal cation, such as magnesium, calcium or iron. A professional is able to identify a large number of suitable substituted or unsubstituted amino-dicarbon acids which can form a stable complex with a bivalent metal cation. It is particularly preferable to use L-glutamic acid or L-aspartic acid as an amino-dicarbonic acid in the method of the invention.

The metal (M) present in the hydrohalogenide of the complex compound, which is the central cation of the complex, can be basically any divalent metal cation. Preferably, the metal (M) is an earth metal, especially magnesium, calcium or strontium, or a heavy metal, especially zinc, iron, manganese, cobalt, copper or cadmium. In the complex according to the invention, the divalent metal cation is complexed as a centralion by the two-way aminodicarbonic acid allylion, forming a chelating complex. Depending on the amino acid and divalent carbonic acid cations, the central amino acid can be bound in varying amounts of water, usually at about 10 molecules per solution. The divalent metal cation is complexed as a centralion by the divalent aminodicarbonic acid allylion, forming a chelating complex.

According to a preferred embodiment of the present invention, the compound of formula (I) is in formula (I) M magnesium, calcium or iron, n 1 or 2, halchlor and m 0, 1, 2 or 3. The compound of formula (I) is in formula (I) M a tertiary metal-L-aspartate hydrohalogenide or a tertiary metal-L-glutamate hydrohalogenide, especially magnesium-L-aspartate hydrochloride or magnesium-L-glutamate hydrochloride, or a hydrate thereof, according to a particularly preferred embodiment. In particular, the use of magnesium-L-aspartate hydrochloride produces an excellent workable product with a specific coarse grain structure and a narrow partial distribution in the process of the invention.

In the method of the invention, in order to achieve the advantageous coarse-grained structure of the complex compound hydrohalogenide, the targeted control of the air entry temperature and the air exit temperature in the spray drying step (b) in combination with an appropriate spray pressure is essential to obtain a granulate with a specifically narrow particle size distribution, good flow and solubility properties and reduced hygroscopicity. Surprisingly, it was found that at an air entry temperature in the range of 300 to 350 °C and an air entry temperature in the range of 100 to 140 °C, a ready-to-use granulate product with a higher dispersibility can be obtained.

The aqueous solution in step (a) may be injected or dried from above or from below into a spray drying tower. The gas used for drying, preferably air, may be directed in direct or counter-current to the sprayed aqueous solution. However, it is preferable to inject the sprayed aqueous solution, which is dried into fine droplets, from above into a spray drying tower and to direct the gas used for drying in direct, i.e. from above downward, to the sprayed aqueous solution. A cyclone and/or filter may then be provided to the air stream to separate the powdered material.

The spray pressure in step (b) of the method of the invention is in the range of about 3 bar to about 5 bar. The spray pressure corresponds to the liquid pressure of the nozzles. The spraying of the solution provided in step (a) is usually done by a single-ply nozzle or hollow nozzle which, at the nozzle exit, creates a hollow cone of liquid, resulting in evenly spaced droplets with a narrow distribution of droplet size.

In a preferred embodiment of the method of the invention, the freshly sprayed particles pass through a flowbed immediately after the spray drying step, for example to reduce residual moisture. When the freshly sprayed particles meet the particles in the flowbed, a granular product of the invention with excellent properties is formed, which is then ejected from the spray tower, preferably by a spill. A subsequent screening step can also be provided. In particular, it is preferable to install a spray tower with an integrated flowbed. The air temperature of the air inlet is preferably in the range of about 110 °C to 100 °C, with the temperature of the product being preferably between 130 °C and 125 °C.The height of the flow bed is not in principle restricted, but is preferably set to 15 cm to 30 cm. The time of stay of the product in the spray dryer is at the discretion of the professional and can be determined mainly by adjusting the height of the overflow and material flow. The material flow rate in the spray drying step is in the range of 50 kg to 200 kg per hour, with a flow rate of 70 kg to 130 kg per hour being preferred.The volume of the water is approximately 8 m3 and is the most commonly used for economic reasons.

The method of manufacture of the granular hydrohalogenide of the complex compound of the present invention produces a product with a very favourable bulk volume, preferably in the range of 150 to 180 ml/100 g, with a bulk volume of about 170 ml/100 g being particularly desirable.

The concentration of the aqueous solution in step (a) is not in principle subject to any special restrictions, but it is preferable to set the concentration of the aqueous solution in step (a) to 0.5 to 3 mol/l, preferably 1 mol/l to 2 mol/l, preferably to about 1.3 mol/l to 1.5 mol/l.

Another subject of the present invention concerns the granulate of a hydrohalogenide of a complex compound composed of a divalent metal cation as the centre and an amino-dicarbonic acid ion and, where appropriate, water as the ligand, where ≤ 10% of the particles have a particle size of < 50 μm and ≤ 10% of the particles have a particle size of > 400 μm, obtained by the method described above.

It is particularly preferable that ≥ 80% of the particles, preferably ≥ 85% of the particles, of the granulate have a particle size in the range of about 100 μm to about 315 μm. Furthermore, it is particularly preferable that ≥ 50% of the particles, preferably ≥ 55% of the particles, of the granulate have a particle size in the range of about 140 μm to about 250 μm. As shown above, the bulk volume [volume of uncompressed product (ml) / 100 g of product] of such a granulate is preferably in the range of 150 to 180 ml/100, with a bulk volume of about 170 ml/100 g being particularly preferable.

The granulate of a hydrohalogenide of a magnesium-containing complex compound obtained by the method of the invention is suitable for use in magnesium therapy and as a feed additive. The granules of such hydrohalogenides of the magnesium complex compounds in question obtained by the method of the invention are valuable pharmaceuticals and feed additives. For example, magnesium L-aspartate hydrochloride is used for targeted magnesium therapy and also as a feed additive and as mineral feed additive for livestock. The compounds can be used in solid granular form or in aqueous solution.

The following examples are given to illustrate the invention in more detail, without limiting it.

Examples Example 1 Manufacture of magnesium L-aspartate hydrochloride

1753 I of demineralised water is presented and stirred with 836 kg of L-aspartic acid. To the resulting dispersion 130 kg of magnesium oxide is added as a powder and the mixture is heated to 60 °C under stirring. Then 628 kg of magnesium chloride (MgCl2•6H2O) is added under stirring and the mixture is heated to 60 °C for 2 h. The solution is then filtered at 60 °C and sprayed at an air inlet temperature of about 320 °C and an air outlet temperature of about 120 °C at a spray pressure of about 4 bar in a Nironet spray dryer.

The final product is a magnesium L-aspartate hydrochloride with the following particle size distribution: < 100μm (6,19%), 100-140μm (19,48%), 140-250μm (57,84%), 250-315μm (10,81%), 315-400μm (4,78%) and 400-500μm (0,90%).

Example 2 Manufacture of magnesium L-glutamate hydrochloride

936 l of demineralised water is heated to 60°C, to which 484 kg of L-glutamic acid is added by stirring. To the resulting dispersion 67 kg of magnesium oxide is added as a powder, in portions, by continuous stirring. The temperature is raised and the solution becomes clear after about 1 h. To this solution a solution of 480 kg of magnesium bromide hexahydrate and 384 I of water (35% solution) is added. A 30% concentration of the complex is set using water. The solution is filtered and then spray-dried under the conditions described in example 1.

Magnesium L-glutamate hydrochloride is obtained as a 100% white powder.

Example 3 Manufacture of calcium L-aspartate hydrochloride

1010 l of demineralised water is heated to 60°C, to which 509 kg L-aspartic acid is added by stirring. To the resulting dispersion 142 kg of calcium hydroxide in the form of a powder are added in portions by continuous stirring. The temperature continues to rise and the solution becomes clear after about 1 h. To this solution we add a solution of 281 kg of calcium chloride dihydrate in 325 l of water (35% solution). With water, the concentration, relative to the complex, is set to 30%.

This is done to obtain calcium L-aspartate hydrochloride in the form of a white powder at 100% yield.

Example 4 Manufacture of zinc-L-aspartate hydrochloride

1025 l of demineralised water is heated to 60°C, to which 464 kg of L-aspartic acid is added by stirring, and 142 kg of zinc oxide is added by stirring the resulting dispersion in portions in the form of a powder.

The temperature rises slightly, but the solution does not become clear, so the temperature is raised to about 90°C, which gives a clear solution.

The resulting solution is added to a solution of 238 kg zinc chloride in 441 l of water (35% solution), the concentration is adjusted to 30% with water, the concentration is adjusted to 30% with water, the solution is filtered and spray-dried as described in example 1, and zinc L-aspartate hydrochloride is obtained as a 100% white powder.

Example 5 Manufacture of magnesium L-aspartate hydrochloride

541 kg L-aspartic acid are dispersed in 1016 I of demineralised water under stirring, heated to 60 °C. To this dispersion 592 kg of 25% by weight hydrochloric acid and then 164 kg of magnesium oxide powder are added and stirred. After a clear solution has been obtained, it is filtered and spray-dried in the manner described in example 1, obtaining magnesium L-aspartate hydrochloride in the form of a 100% white powder.

Claims (12)

1. Process for preparing a granular hydrohalide of a complex compound which is composed of a divalent metal cation as central ion and of an amino dicarboxylic acid ion and, where appropriate, water as ligand comprising the steps:

   (a) preparation of an aqueous solution of the hydrohalide of the complex compound,

   (b) spray drying of the aqueous solution obtained in step (a) at an air inlet temperature of from 300 to 350°C and at an air outlet temperature of from 100 to 140°C and with a spraying pressure of from 3 to 5 bar.
2. Process according to Claim 1, where the freshly sprayed particles after step (b) are passed through a fluidized bed to reduce the residual moisture, and are subjected where appropriate subsequently to a sieving step.
3. Process according to Claim 1 or 2, where the hydrohalide of the complex compound is prepared by reacting an amino dicarboxylic acid with a hydroxide, oxide and/or carbonate of the metal (M) in aqueous solution and further reaction of the resulting aqueous solution or suspension with a halide of the metal (M) and/or hydrohalic acid,
4. Process according to any of Claims 1 to 3, where the hydrohalide of the complex compound is a compound shown in formula (I) below: in which M²⁺ is a divalent metal cation, Hal^- is a halide ion, n is 1 or 2 and m is 0 to 10.
5. Process according to any of Claims 1 to 4, where the amino dicarboxylic acid is L-glutamic acid or L-aspartic acid.
6. Process according to any of Claims 1 to 5, where the divalent metal (M) is an alkaline earth metal or a heavy metal.
7. Process according to any of Claims 1 to 5, where the hydrohalide of the complex compound is an alkaline earth metal L-aspartate hydrohalide or an alkaline earth metal L-glutamate hydrohalide.
8. Process according to any of Claims 1 to 7, where the hydrohalide of the complex compound is magnesium L-aspartate hydrochloride or magnesium L-glutamte hydrochloride.
9. Process according to any of Claims 1 to 8, where the concentration of the aqueous solution in step (a) is set at from 0.5 mol/l to 3 mol/l.
10. Granules of a hydrohalide of a complex compound which is composed of a divalent metal cation as ≤ 10% of the particles have a particle size of < 50 µm and ≤ 10% of the particles have a particle size of > 400 µm, obtained by the process defined in any of Claims 1 to 9.
11. Granules according to Claim 10, where ≥ 80% of the particles have a particle size in a range from about 100 µm to about 315 µm.
12. Granular hydrohalide according to Claim 10 or 11, where ≥ 50% of the particles have a particle size in a range from about 140 µm to about 250 µm.