CA2516147C - Process for preparing certain hydrohalide metal complex compounds having a specific coarse structure - Google Patents
Process for preparing certain hydrohalide metal complex compounds having a specific coarse structure Download PDFInfo
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- CA2516147C CA2516147C CA002516147A CA2516147A CA2516147C CA 2516147 C CA2516147 C CA 2516147C CA 002516147 A CA002516147 A CA 002516147A CA 2516147 A CA2516147 A CA 2516147A CA 2516147 C CA2516147 C CA 2516147C
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- hydrohalide
- complex compound
- aqueous solution
- magnesium
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- -1 metal complex compounds Chemical class 0.000 title claims abstract description 38
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 8
- 239000002245 particle Substances 0.000 claims abstract description 42
- 229910052751 metal Inorganic materials 0.000 claims abstract description 33
- 239000002184 metal Substances 0.000 claims abstract description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 150000001768 cations Chemical class 0.000 claims abstract description 20
- 150000002500 ions Chemical class 0.000 claims abstract description 14
- 239000003446 ligand Substances 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims description 35
- 150000001875 compounds Chemical class 0.000 claims description 32
- 239000007864 aqueous solution Substances 0.000 claims description 26
- QYOBXHXZJRPWDE-JIZZDEOASA-L magnesium;(2s)-2-amino-4-hydroxy-4-oxobutanoate;chloride Chemical compound [Mg+2].Cl.[O-]C(=O)[C@@H](N)CC([O-])=O QYOBXHXZJRPWDE-JIZZDEOASA-L 0.000 claims description 23
- 239000008187 granular material Substances 0.000 claims description 16
- 238000001694 spray drying Methods 0.000 claims description 14
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 12
- 229910052749 magnesium Inorganic materials 0.000 claims description 12
- 239000011777 magnesium Substances 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- 238000005507 spraying Methods 0.000 claims description 9
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 7
- 239000007900 aqueous suspension Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 7
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 claims description 6
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 claims description 6
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 6
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 6
- 229960005261 aspartic acid Drugs 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 150000004820 halides Chemical class 0.000 claims description 4
- WQAQVZMASSANIM-QTNFYWBSSA-L magnesium;(2s)-2-amino-5-hydroxy-5-oxopentanoate;chloride Chemical compound [Mg+2].Cl.[O-]C(=O)[C@@H](N)CCC([O-])=O WQAQVZMASSANIM-QTNFYWBSSA-L 0.000 claims description 4
- 238000007873 sieving Methods 0.000 claims description 4
- 229960002989 glutamic acid Drugs 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 229930195714 L-glutamate Natural products 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 229910001385 heavy metal Inorganic materials 0.000 claims description 2
- 238000009826 distribution Methods 0.000 abstract description 12
- 150000003839 salts Chemical class 0.000 abstract description 5
- 239000000243 solution Substances 0.000 description 24
- 239000000047 product Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- 239000000843 powder Substances 0.000 description 9
- 239000007921 spray Substances 0.000 description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000006185 dispersion Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 229960005069 calcium Drugs 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910052742 iron Inorganic materials 0.000 description 3
- 239000000395 magnesium oxide Substances 0.000 description 3
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 3
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 3
- 229910001507 metal halide Inorganic materials 0.000 description 3
- 150000005309 metal halides Chemical class 0.000 description 3
- 229910000000 metal hydroxide Inorganic materials 0.000 description 3
- 229910044991 metal oxide Inorganic materials 0.000 description 3
- 150000004706 metal oxides Chemical class 0.000 description 3
- 239000012254 powdered material Substances 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- LUUAAIHWKUJNKC-JIZZDEOASA-L calcium;(2s)-2-aminobutanedioate;hydrochloride Chemical compound Cl.[Ca+2].[O-]C(=O)[C@@H](N)CC([O-])=O LUUAAIHWKUJNKC-JIZZDEOASA-L 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- RXROUXYOFRZVLU-JIZZDEOASA-L zinc;(2s)-2-aminobutanedioate;hydrochloride Chemical compound Cl.[Zn+2].[O-]C(=O)[C@@H](N)CC([O-])=O RXROUXYOFRZVLU-JIZZDEOASA-L 0.000 description 2
- 101100065878 Caenorhabditis elegans sec-10 gene Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052793 cadmium Inorganic materials 0.000 description 1
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 description 1
- LLSDKQJKOVVTOJ-UHFFFAOYSA-L calcium chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Ca+2] LLSDKQJKOVVTOJ-UHFFFAOYSA-L 0.000 description 1
- 229940052299 calcium chloride dihydrate Drugs 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 150000004697 chelate complex Chemical class 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- RXMQCXCANMAVIO-CEOVSRFSSA-L magnesium;(2s)-2-amino-4-hydroxy-4-oxobutanoate Chemical compound [H+].[H+].[Mg+2].[O-]C(=O)[C@@H](N)CC([O-])=O.[O-]C(=O)[C@@H](N)CC([O-])=O RXMQCXCANMAVIO-CEOVSRFSSA-L 0.000 description 1
- LGLXXNHIGIJYQQ-UHFFFAOYSA-L magnesium;dibromide;hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[Br-].[Br-] LGLXXNHIGIJYQQ-UHFFFAOYSA-L 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 229940029985 mineral supplement Drugs 0.000 description 1
- 235000020786 mineral supplement Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/142—Amino acids; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/20—Inorganic substances, e.g. oligoelements
- A23K20/24—Compounds of alkaline earth metals, e.g. magnesium
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K40/00—Shaping or working-up of animal feeding-stuffs
- A23K40/10—Shaping or working-up of animal feeding-stuffs by agglomeration; by granulation, e.g. making powders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/003—Compounds containing elements of Groups 2 or 12 of the Periodic Table without C-Metal linkages
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Polymers & Plastics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Food Science & Technology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Zoology (AREA)
- Medicinal Chemistry (AREA)
- Animal Husbandry (AREA)
- Epidemiology (AREA)
- Obesity (AREA)
- Inorganic Chemistry (AREA)
- Nutrition Science (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Glanulating (AREA)
- Manufacture Of Metal Powder And Suspensions Thereof (AREA)
Abstract
The present invention relates to a process for preparing a granular hydrohalide salt of a particular metal 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, where the hydrohalide salt is obtained with a specific particle size distribution.
Description
TITLE: PROCESS FOR PREPARING CERTAIN HYDROHALIDE METAL
COMPLEX COMPOUNDS HAVING A SPECIFIC COARSE STRUCTURE
BACKGROUND
The present invention relates to a process for preparing a granular hydrohalide salt of a particular metal 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, where the hydrohalide salt is obtained with a specific particle size distribution.
Complexes of a divalent metal cation as central ion and of an amino dicarboxylic acid ligand, and the hydrohalides thereof and various processes for preparing them are known. Complexes of a divalent metal cation as central ion and of an amino dicarboxylic acid ligand, for example magnesium L-aspartate can be handled substantially without problems. In contrast thereto, the hydrohalides thereof, especially magnesium L-aspartate hydrochloride, are usually very hygroscopic, so that they can be prepared only at extremely low humidity. Magnesium L-aspartate hydrochloride liquefies even at a humidity of more than 50%, making its further processing extremely difficult or even impossible. Further processing to tablets or granules is accordingly possible only in air-conditioned zones with controlled low humidity. Because of the extreme hygroscopicity, it has been possible to date to granulate in particular magnesium L-aspartate hydrochloride only using organic solvents, which is undesired for environmental reasons.
In order to solve the problem of the hygroscopicity of the hydrohalides described above, attempts have been made to prepare a granular product with a reduced total surface area. All attempts made to date to prepare a granular product by spray drying have, however, provided an inadequate, usually very finely powdered material which, because of the large surface area or the high proportion of very finely powdered material, rapidly assumes a honey-like consistency, making further processing impossible. For example, a very finely powdered material is obtained under the spray-drying conditions (air inlet temperature: about 180 C;
air outlet temperature: about 120 C) indicated in DE 32 38 118 Al (cf. Examples 1 to 5 of DE 32 38 118 Al).
The present invention is thus based on the technical object of providing hydrohalides of complex compounds which are composed of a divalent metal cation as central ion and of an amino dicarboxylic acid ion and, where appropriate, water as ligand, and which are intended to have good flow and dissolving properties and reduced hygroscopicity.
This object is achieved by providing the embodiments characterized in the claims.
According to an aspect of the present invention is a 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 is provided and comprises 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.
COMPLEX COMPOUNDS HAVING A SPECIFIC COARSE STRUCTURE
BACKGROUND
The present invention relates to a process for preparing a granular hydrohalide salt of a particular metal 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, where the hydrohalide salt is obtained with a specific particle size distribution.
Complexes of a divalent metal cation as central ion and of an amino dicarboxylic acid ligand, and the hydrohalides thereof and various processes for preparing them are known. Complexes of a divalent metal cation as central ion and of an amino dicarboxylic acid ligand, for example magnesium L-aspartate can be handled substantially without problems. In contrast thereto, the hydrohalides thereof, especially magnesium L-aspartate hydrochloride, are usually very hygroscopic, so that they can be prepared only at extremely low humidity. Magnesium L-aspartate hydrochloride liquefies even at a humidity of more than 50%, making its further processing extremely difficult or even impossible. Further processing to tablets or granules is accordingly possible only in air-conditioned zones with controlled low humidity. Because of the extreme hygroscopicity, it has been possible to date to granulate in particular magnesium L-aspartate hydrochloride only using organic solvents, which is undesired for environmental reasons.
In order to solve the problem of the hygroscopicity of the hydrohalides described above, attempts have been made to prepare a granular product with a reduced total surface area. All attempts made to date to prepare a granular product by spray drying have, however, provided an inadequate, usually very finely powdered material which, because of the large surface area or the high proportion of very finely powdered material, rapidly assumes a honey-like consistency, making further processing impossible. For example, a very finely powdered material is obtained under the spray-drying conditions (air inlet temperature: about 180 C;
air outlet temperature: about 120 C) indicated in DE 32 38 118 Al (cf. Examples 1 to 5 of DE 32 38 118 Al).
The present invention is thus based on the technical object of providing hydrohalides of complex compounds which are composed of a divalent metal cation as central ion and of an amino dicarboxylic acid ion and, where appropriate, water as ligand, and which are intended to have good flow and dissolving properties and reduced hygroscopicity.
This object is achieved by providing the embodiments characterized in the claims.
According to an aspect of the present invention is a 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 is provided and comprises 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.
According to another aspect of the present invention is a 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, by reacting an amino dicarboxylic acid with a hydroxide, oxide and/or carbonate of the metal (M) in aqueous solution or suspension with a halide of the metal (M) and/or hydrohalic acid; (b) spray drying of the aqueous solution obtained in step (a) at a 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, and wherein 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.
2a BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a graph showing the particle size distribution of finely powdered magnesium L-aspartate hydrochloride prepared by a standard process disclosed in DE 32 38 118 Al.
Fig. 2 is a graph showing the particle size distribution of granular magnesium L-aspartate hydrochloride prepared by the process according to the invention.
Fig. 3 a graphical representation of the measurements shown in Table 5.
DETAILED DESCRIPTION
The hydrohalides of the complex compounds prepared according to the invention can be prepared in various ways. For example, they can be prepared by mixing equimolar amounts of a metal salt of an amino dicarboxylic acid (with a divalent metal such as, for example, magnesium) and an appropriate metal halide in aqueous solution. However, it is preferred to prepare the hydrohalides of the complex compounds by reacting an amino dicarboxylic acid with a hydroxide, oxide and/or carbonate of the metal (M) in aqueous solution and further reacting the resulting aqueous solution or suspension with a halide of the metal (M) and/or hydrohalic acid. The latter preparation process can start from more favourable and easily available starting compounds, making the overall process more economic.
It is particularly preferred to mix an aqueous solution or suspension of 2 mol of the particular amino dicarboxylic acid with an aqueous solution or suspension of 1 mol of the appropriate metal oxide, hydroxide and/or carbonate and with an aqueous solution or suspension of 1 mol of the appropriate metal halicte, and to stir until a clear solution is obtained. Instead of the metal halide it is also possible to use an equimolar amount of a hydrohalic acid and of a metal oxide, hydroxide and/or carbonate. The mixing preferably takes place in a temperature range from about 20 to about 90 C, or in the case of an exothermic reaction at slightly elevated temperature until a clear solution is obtained, which can be purified by filtration. It may be advantageous in some cases firstly to mix the solution or suspension of the amino dicarboxylic acid with the metal oxide, hydroxide or carbonate as solid, solution or suspension and only then, when a clear solution has been obtained, to add the solution of the metal halide.
The hydrohalide of the complex compound is preferably a compound characterized by formula (I) below:
Hal 0 0 ~ (CHz)~
(H20) m ~, MZ; CH
-0. +
C
Formula (I) in which M2+ is a divalent metal cation, Hal" is a halide ion such as fluoride, chloride, bromide or iodide, n is 1 or 2 and m is 0 to 10, preferably 0, 1, 2 or 3.
The amino dicarboxylic acids which can be used are subject to no particular restrictions as long as they are able to form a chelate with a divalent metal cation such as, for example, magnesium, calcium or iron. A
skilled person is able to find a large number of suitable substituted or unsubstitutea amino dicarboxylic acids able to form a stable complex with a divalent metal cation. It is particularly preferred to use L-glutamic acid or L-aspartic acid as amino-dicarboxylic acid in the process according to the irivention.
The metal (M) which is present in the hydrohalide of the complex compound and which represents the central cation of the complex can in principle be any divalent metal cation. The metal (M) is preferably an alkaline earth metal, in particular magnesium, calcium or strontium, or a heavy metal, in particular zinc, iron, manganese, cobalt, copper or cadmium. In the complex obtained according to the invention, the divalent metal cation is complexed as central ion by the bidentate amino dicarboxylic acid ligand to form a chelate complex. Depending on the central ion and amino dicarboxylic acid ligand, varying amounts of water may be bound, normally up to about 10 molecules per metal cation. The hydrohalide results through protonation of the amino group of the amino dicarboxylic acid ligand, the counter ion which is bound being a halide ion such as fluoride, chloride, bromide or iodide.
In a preferred embodiment of the present invention, M
in the above formula (I) is magnesium, calcium or iron, n is 1 or 2, Hal is chlorine and m is 0, 1, 2 or 3. The compound of the formula (I) is in a particularly preferred embodiment an alkaline earth metal L-aspartate hydrohalide or an alkaline earth metal L-glutamate hydrohalide, in particular magnesium L-aspartate hydrochloride or magnesium L-glutamate hydrochloride, or a hydrate thereof. The use of magnesium L-aspartate hydrochloride in particular in the process according to the invention results in an excellently processable product having a specifically coarse structure and a narrow parcicie sl:6e distribution.
In the process according to the invention, it is essential for achieving the advantageous coarse structure of the hydrohalide of the complex compound that the air inlet temperature and the air outlet temperature in the spray-drying step (b) are controlled in a targeted manner in combination with a suitable spraying pressure in order to obtain granules with a specifically narrow particle size distribution, good flow and dissolving properties and a reduced hygroscopicity. It has surprisingly been found that with an air inlet temperature in a range from 300 to 350 C and with an air outlet temperature in a range from 100 to 140 C it is possible to obtain a stable granular product with excellent further processability when the aqueous solution is sprayed or atomized with a spraying pressure in a range from about 3 to about 5 bar. The exact temperature within these ranges depends on the hydrohalide to be subjected to the spray drying. However, a skilled person is capable of accurate setting within the above ranges. It is furthermore surprising in this connection that, despite the use of a comparatively high air inlet temperature, a coarse product is obtained.
The aqueous solution in step (a) can be sprayed or atomized into the top or bottom of a spray-drying tower. The gas used for drying, preferably air, can be passed cocurrently or countercurrently to the sprayed aqueous solution. However, it is preferred for the sprayed aqueous solution, which is atomized to fine droplets, to be sprayed into the top of a spray-drying tower, and for the gas used for drying to be passed cocurrently thereto, i.e. from the top to the bottom.
Subsequent to the air outlet it is possible to provide a cyclone and/or a filter in order to separaLe a Line powdery material.
The spraying pressure in step (b) of the process according to the invention is in a range from about 3 bar to about 5 bar. The spraying pressure corresponds to the liquid inlet pressure of the nozzles. The atomization of the solution prepared in step (a) normally takes place through a single fluid nozzle or hollow cone nozzle which generates a hollow cone of liquid at the outlet from the nozzle, resulting in uniform droplets with a narrow droplet size distribution.
In a preferred embodiment of the process according to the invention, the freshly sprayed particles pass immediately after the spray-drying step through a fluidized bed in order for example to reduce the residual moisture. When the freshly sprayed particles impinge on the fluidized bed particles there is formation of a granular product according to the invention with excellent properties, which is subsequently discharged from the spray tower, preferably over a weir. A further possibility is to provide a subsequent sieving step. It is particularly preferred to provide a spray tower with integrated fluidized bed. The air inlet temperature to the fluidized bed is preferably in a range from 110 to 130 C, with the temperature of the product in the fluidized bed preferably being adjusted to about 100 to 125 C. The height of the fluidized bed is not in principle subject to special restrictions but is preferably set at from 15 cm to 30 cm. The setting of the holdup time of the product in the spray drier is within the routine judgement of a skilled person and can be determined in particular by adjusting the height of the wheel and the material throughput. The material throughput in the spray-drying step is in a range Lrum 50 kg to 200 kg per hour, a preferred throughput being from 70 kg to 130 kg per hour. The volume of the spray drier is subject to no particular restrictions.
However, it is preferably in a range from about 5 to 20 m3, with a volume of about 8 m3 being used most often for economic reasons.
A product with a very favourable apparent volume can be achieved in the process according to the invention for preparing the granular hydrohalide of the complex compound of relevance here. The apparent volume [volume of the uncompressed product (ml)/100 g of the product]
is preferably in a range from 150 to 180 ml/100 g, with a particularly preferred apparent volume being about 170 ml/100 g.
The concentration of the aqueous solution in step (a) is subject in principle to no particular restrictions.
However, it is preferred to adjust the concentration of the aqueous solution in step (a) to from 0.5 to 3 mol/1, preferably 1 mol/l to 2 mol/l, particularly preferably to about 1.3 mol/l to 1.5 mol/l.
The present invention further relates to the granules of a 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, where 5 10% of the particles have a particle size of < 50 m and 5 10% of the particles have a particle size. of > 400 m, obtained by the process according to the invention described above.
It is particularly preferred for _ 70%, even more preferred ? 80%, of the particles, with preference ? 85% of the particles, of the granules to have a particle size in a range from about 100 m to about 315 m. It is further particularly preferred for _ 50%
of the particles, with preference >_ 55% of the particles, of the granules to have a particle size in a range from about 140 m to about 250 m. As stated above, the apparent volume [volume of the uncompressed product (ml)/100 g of the product] of such granules is preferably in a range from 150 to 180 ml/100 g, with a particularly preferred apparent volume being about 170 ml/100 g.
The present invention additionally relates to the use of the granules, prepared by the process according to the invention, of a hydrohalide of a magnesium-containing complex compound in magnesium therapy and as addition to animal feed. The granules obtained according to the invention of such hydrohalides of the magnesium complex compounds of relevance here are valuable pharmaceuticals and additions to animal feed.
Thus, for example, magnesium L-aspartate hydrochloride is employed for targeted magnesium therapy and also as addition to animal feed and also as mineral supplement for productive livestock. The compounds can be employed in solid granular form or in aqueous solution.
The following examples are indicated in order to explain the invention in more detail without restricting it thereby.
Examples Example 1 Preparation of magnesium L-aspartate hydrochloride 836 kg of L-aspartic acid are added with stirring to 1753 1 of demineralized water. 130 kg of magnesium oxide as powder are added to the resulting dispersion, and the mixture is heated to 60 C with stirring. Then, while stirring, 628 g oz magnesium CnlULlUC 11=ly-1.2-U112-are added, and the mixture is heated with stirring at 60 C for 2 h. The solution is subsequently filtered at 60 C and spray dried with an air inlet temperature of about 320 C and an air outlet temperature of about 1200C with a spraying pressure of about 4 bar in a Niro spray drier.
The final product obtained is a magnesium L-aspartate hydrochloride having the following particle size distribution: < 100 m (6.19%), 100-140 m (19.48%), 140-250 m (57.84%), 250-315 m (10.81%), 315-400 m (4.78%) and 400-500 m (0.90%) . The apparent volume of this final product was 170m1/100 g.
Example 2 Preparation of magnesium L-glutamate hydrochloride 936 1 of demineralized water are heated to 60 C, after which 484 kg of L-glutamic acid are added with stirring. 67 kg of magnesium oxide are added as powder in portions to the resulting dispersion while stirring continuously. The temperature rises, and the solution becomes clear after about 1 h. A solution of 480 kg of magnesium bromide hexahydrate and 384 1 of water (35%
strength solution) is added to this solution. The concentration of the complex is adjusted to 30% by using water. The solution is filtered and then spray dried under the conditions described in Example 1.
This results in magnesium L-glutamate hydrochloride as a white powder in 100% yield.
Example 3 Preparation of calcium L-aspartate hydrochloride 1010 1 of demineralized water are heated to 60 C, after which 509 kg of L-aspartic acid are aaaea Wi111C
stirring. 142 kg of calcium hydroxide are added in the form of a powder in portions to the resulting dispersion while stirring continuously. The temperature rises further and the solution becomes clear after about 1 h. A solution of 281 kg of calcium chloride dihydrate in 325 1 of water (35% strength solution) is added to this solution. The concentration based on the complex is adjusted to 30% with water. This is followed by filtration and spray drying in the manner described iri Example 1.
This results in calcium L-aspartate hydrochloride in the form of a white powder in 100% yield.
Example 4 Preparation of zinc L-aspartate hydrochloride 1025 1 of demineralized water are heated to 60 C, after which 464 kg of L-aspartic acid are added while stirring. 142 kg of zinc oxide in the form of a powder are added in portions to the resulting dispersion with continuous stirring. The temperature rises somewhat, but the solution does not become clear. The temperature is therefore raised to about 90 C, after which a clear solution is obtained. The concentration is adjusted to 30% by adding water.
A solution of 238 kg of zinc chloride in 441 1 of water (35% strength solution) is added to the resulting solution. The concentration based on the complex is adjusted to 30% with water. This is followed by filtration and spray drying in the manner described in Example 1. This results in zinc L-aspartate hydrochloride in the form of a white powder in 100%
yield.
Example 5 Preparation of magnesium L-aspartate hydrochloride 541 kg of L-aspartic acid are dispersed in 1016 1 of demineralized water by stirring with heating to 60 C.
592 kg of a 25% by weight hydrochloric acid and then 164 kg of magnesium oxide as powder are added to this dispersion and stirred. After a clear solution has been obtained, it is filtered and spray dried in the manner described in Example 1, resulting. in magnesium L-aspartate hydrochloride in the form of a white powder in 100% yield.
Example 6 (particle size distribution) The particle size distribution of granular magnesium L-aspartate hydrochloride prepared by the process according to the invention was compared with a finely powdered magnesium L-aspartate hydrochloride prepared by a standard process (disclosed in DE 32 38 118 A1).
The comparative sieve analyses were performed using a Hosokawa Alpine air jet sieve, and the results are shown in Tables 1 and 2 below.12 ~ O O O
b 00 00 N
y~ r1 r-I ~--I
u O O O
Ow O 00 co CN
0 ~ U1 I- O
a a M m in Ln ,r LO
4J O f"1 %D
z O N N
V tIl N ~
H
_ O M a' w O Cl1 b ~ N ~
ro ri O O O O
r-i ro H
a w 00 N
1 O ~
r-I oM O Ln ..~ ~..{
^O o d~ N C9 a ui 0; w ow 0 rn fA co to N
tfl M lfl =
Lfl N r-1 ~
O O
r{
U kO arn v ~4 0 O ~-I N M
z The minimum particle size (dmin) was 0.7 m, tne maximum particle size (dmax)was 260.0 m and the average particle size (d50) was 54.9 m. Figure 1 shows the graphical representation of the particle size distribution of finely powdered magnesium L-aspartate hydrochloride prepared by a standard process disclosed iri DE 32 38 118 Al.
1J ri r~ r~ ri ~-1 r~
a 0 rl ri ri r~ ri r-1 ~ . .
H N m O O O O
a X r-I ri r1 N N N N
m O Q1 ~0 L1l GO ~ al d~
O 0~ Ol 4 M
=
d $4 ZLn V w 14 1-4 O
a~
O m o rn~ ui %D rn-:r 43 O o; rn cf+ r~ ~, a Ln Ln a .r., b ~4 ~Jl O 0 0 0 O 0 0 0 U H
rt W
O
a a, - 00 N O l0 N a0 W
I i O
0 ~- oW O Ol 0~ oD N O~ (7 O
q o cv co O ct+ a0 N N
~ a o 0 O O r N O O 01 fa r~ I- m 01 41 H
N lp N C~ d' d~ O 00 ~
o~ 0 O ~ ~ ~ tfl M O
I0000.O.cØ
N 0 0 N t!1 O O
lfl r-I rl O O
~ u k0 O% rl N M d' Lfl ~
0 0 r=1 N Md' Ltl l0 Il z L, The minimum particle size (amin) was 4ts. u m, UiuC
maximum particle size (d,,,,,.)was 448.7 m and the average particle size (d50) was 250.8 m. Figure 2 shows the graphical representation of the particle size distribution of granular magnesium L-aspartate hydrochloride prepared by the process according to the invention.
Example 7 (flow time and flowability) The flowability of granular magnesium L-aspartate hydrochloride prepared by the process according to the invention was compared with a finely powdered magnesium L-aspartate hydrochloride prepared by a standard process (disclosed in DE 32 38 118 A1). The test arrangement consisted of a conical flow funnel with a height of 22.5 cm, an upper internal diameter of 7.3 cm and a lower internal diameter of 8.2 mm. The test was carried out by the 2.9.16 Method, Ph. Eur., 4th edition, main volume 2002, as follows. 100 g portions of material were put into the funnel. Opening of the funnel orifice was followed by assessment of the flowability, and the time for the whole sample to flow out of the funnel was determined. Two samples were measured in each case. The results are shown in Table 3 below.
Table 3 (flowability) Preparation Standard Standard According According process to the to the invention invention Flowability uneven, uneven, free free not free- not free- flowing flowing flowing flowing Flow time Cannot be cannot be 10 sec 10 sec determined determined Example 8 (dissolving properties) The dissolving properties of granular magnesium L-aspartate hydrochloride prepared by the process according to the invention were compared with a finely powdered magnesium L-aspartate hydrochloride prepared by a standard process (disclosed in DE 32 38 118 A1).
The test arrangement consisted of a glass beaker with stirring bar which was adjusted to 20 revolutions per min. 250 ml of water were introduced and then 10 g of test material were added with the stirrer motor running. The time until dissolution was complete was measured. The results are shown in Table 4 below.
Table 4 (dissolving properties) Preparation Standard Standard According According process to the to the invention invention Dissolving 7 min 7 min 3 min 2 min time Example 9 (water uptake capacity or hygroscopicity) The hygroscopicity of granular magnesium L-aspartate hydrochloride prepared by the process according to the invention was compared with a finely powdered magnesium L-aspartate hydrochloride prepared by a standard process (disclosed in DE 32 38 118 A1). The test arrangement consisted of a desiccator which was adjusted to a relative humidity of 75% with a saturated sodium chloride solution. In each case a defined amount of sample was weighed out and the sample dish was placed in the desiccator. The percentage increase in weight of the weighed amount was determined after 2, 4, 5 and 20 hours. The results are shown in Table S below, from which it is unambiguously evident that the hygroscopicity of the granules according to the invention is distinctly reducect comparea wirn a 1111e1y powdered product according to the prior art. Figure 3 shows a graphical representation of the measurements shown in Table 5.
Table 5 (hygroscopicity) Testing Standard Standard According According time to the to the invention invention 2 h 0.35 0.30 0.18 0.16 4 h 0.63 0.55 0.33 0.30 5 h 0.72 0.71 0.43 0.40 20 h 3.06 2.70 1.74 1.63
(a) preparation of an aqueous solution of the hydrohalide of the complex compound, by reacting an amino dicarboxylic acid with a hydroxide, oxide and/or carbonate of the metal (M) in aqueous solution or suspension with a halide of the metal (M) and/or hydrohalic acid; (b) spray drying of the aqueous solution obtained in step (a) at a 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, and wherein 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.
2a BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a graph showing the particle size distribution of finely powdered magnesium L-aspartate hydrochloride prepared by a standard process disclosed in DE 32 38 118 Al.
Fig. 2 is a graph showing the particle size distribution of granular magnesium L-aspartate hydrochloride prepared by the process according to the invention.
Fig. 3 a graphical representation of the measurements shown in Table 5.
DETAILED DESCRIPTION
The hydrohalides of the complex compounds prepared according to the invention can be prepared in various ways. For example, they can be prepared by mixing equimolar amounts of a metal salt of an amino dicarboxylic acid (with a divalent metal such as, for example, magnesium) and an appropriate metal halide in aqueous solution. However, it is preferred to prepare the hydrohalides of the complex compounds by reacting an amino dicarboxylic acid with a hydroxide, oxide and/or carbonate of the metal (M) in aqueous solution and further reacting the resulting aqueous solution or suspension with a halide of the metal (M) and/or hydrohalic acid. The latter preparation process can start from more favourable and easily available starting compounds, making the overall process more economic.
It is particularly preferred to mix an aqueous solution or suspension of 2 mol of the particular amino dicarboxylic acid with an aqueous solution or suspension of 1 mol of the appropriate metal oxide, hydroxide and/or carbonate and with an aqueous solution or suspension of 1 mol of the appropriate metal halicte, and to stir until a clear solution is obtained. Instead of the metal halide it is also possible to use an equimolar amount of a hydrohalic acid and of a metal oxide, hydroxide and/or carbonate. The mixing preferably takes place in a temperature range from about 20 to about 90 C, or in the case of an exothermic reaction at slightly elevated temperature until a clear solution is obtained, which can be purified by filtration. It may be advantageous in some cases firstly to mix the solution or suspension of the amino dicarboxylic acid with the metal oxide, hydroxide or carbonate as solid, solution or suspension and only then, when a clear solution has been obtained, to add the solution of the metal halide.
The hydrohalide of the complex compound is preferably a compound characterized by formula (I) below:
Hal 0 0 ~ (CHz)~
(H20) m ~, MZ; CH
-0. +
C
Formula (I) in which M2+ is a divalent metal cation, Hal" is a halide ion such as fluoride, chloride, bromide or iodide, n is 1 or 2 and m is 0 to 10, preferably 0, 1, 2 or 3.
The amino dicarboxylic acids which can be used are subject to no particular restrictions as long as they are able to form a chelate with a divalent metal cation such as, for example, magnesium, calcium or iron. A
skilled person is able to find a large number of suitable substituted or unsubstitutea amino dicarboxylic acids able to form a stable complex with a divalent metal cation. It is particularly preferred to use L-glutamic acid or L-aspartic acid as amino-dicarboxylic acid in the process according to the irivention.
The metal (M) which is present in the hydrohalide of the complex compound and which represents the central cation of the complex can in principle be any divalent metal cation. The metal (M) is preferably an alkaline earth metal, in particular magnesium, calcium or strontium, or a heavy metal, in particular zinc, iron, manganese, cobalt, copper or cadmium. In the complex obtained according to the invention, the divalent metal cation is complexed as central ion by the bidentate amino dicarboxylic acid ligand to form a chelate complex. Depending on the central ion and amino dicarboxylic acid ligand, varying amounts of water may be bound, normally up to about 10 molecules per metal cation. The hydrohalide results through protonation of the amino group of the amino dicarboxylic acid ligand, the counter ion which is bound being a halide ion such as fluoride, chloride, bromide or iodide.
In a preferred embodiment of the present invention, M
in the above formula (I) is magnesium, calcium or iron, n is 1 or 2, Hal is chlorine and m is 0, 1, 2 or 3. The compound of the formula (I) is in a particularly preferred embodiment an alkaline earth metal L-aspartate hydrohalide or an alkaline earth metal L-glutamate hydrohalide, in particular magnesium L-aspartate hydrochloride or magnesium L-glutamate hydrochloride, or a hydrate thereof. The use of magnesium L-aspartate hydrochloride in particular in the process according to the invention results in an excellently processable product having a specifically coarse structure and a narrow parcicie sl:6e distribution.
In the process according to the invention, it is essential for achieving the advantageous coarse structure of the hydrohalide of the complex compound that the air inlet temperature and the air outlet temperature in the spray-drying step (b) are controlled in a targeted manner in combination with a suitable spraying pressure in order to obtain granules with a specifically narrow particle size distribution, good flow and dissolving properties and a reduced hygroscopicity. It has surprisingly been found that with an air inlet temperature in a range from 300 to 350 C and with an air outlet temperature in a range from 100 to 140 C it is possible to obtain a stable granular product with excellent further processability when the aqueous solution is sprayed or atomized with a spraying pressure in a range from about 3 to about 5 bar. The exact temperature within these ranges depends on the hydrohalide to be subjected to the spray drying. However, a skilled person is capable of accurate setting within the above ranges. It is furthermore surprising in this connection that, despite the use of a comparatively high air inlet temperature, a coarse product is obtained.
The aqueous solution in step (a) can be sprayed or atomized into the top or bottom of a spray-drying tower. The gas used for drying, preferably air, can be passed cocurrently or countercurrently to the sprayed aqueous solution. However, it is preferred for the sprayed aqueous solution, which is atomized to fine droplets, to be sprayed into the top of a spray-drying tower, and for the gas used for drying to be passed cocurrently thereto, i.e. from the top to the bottom.
Subsequent to the air outlet it is possible to provide a cyclone and/or a filter in order to separaLe a Line powdery material.
The spraying pressure in step (b) of the process according to the invention is in a range from about 3 bar to about 5 bar. The spraying pressure corresponds to the liquid inlet pressure of the nozzles. The atomization of the solution prepared in step (a) normally takes place through a single fluid nozzle or hollow cone nozzle which generates a hollow cone of liquid at the outlet from the nozzle, resulting in uniform droplets with a narrow droplet size distribution.
In a preferred embodiment of the process according to the invention, the freshly sprayed particles pass immediately after the spray-drying step through a fluidized bed in order for example to reduce the residual moisture. When the freshly sprayed particles impinge on the fluidized bed particles there is formation of a granular product according to the invention with excellent properties, which is subsequently discharged from the spray tower, preferably over a weir. A further possibility is to provide a subsequent sieving step. It is particularly preferred to provide a spray tower with integrated fluidized bed. The air inlet temperature to the fluidized bed is preferably in a range from 110 to 130 C, with the temperature of the product in the fluidized bed preferably being adjusted to about 100 to 125 C. The height of the fluidized bed is not in principle subject to special restrictions but is preferably set at from 15 cm to 30 cm. The setting of the holdup time of the product in the spray drier is within the routine judgement of a skilled person and can be determined in particular by adjusting the height of the wheel and the material throughput. The material throughput in the spray-drying step is in a range Lrum 50 kg to 200 kg per hour, a preferred throughput being from 70 kg to 130 kg per hour. The volume of the spray drier is subject to no particular restrictions.
However, it is preferably in a range from about 5 to 20 m3, with a volume of about 8 m3 being used most often for economic reasons.
A product with a very favourable apparent volume can be achieved in the process according to the invention for preparing the granular hydrohalide of the complex compound of relevance here. The apparent volume [volume of the uncompressed product (ml)/100 g of the product]
is preferably in a range from 150 to 180 ml/100 g, with a particularly preferred apparent volume being about 170 ml/100 g.
The concentration of the aqueous solution in step (a) is subject in principle to no particular restrictions.
However, it is preferred to adjust the concentration of the aqueous solution in step (a) to from 0.5 to 3 mol/1, preferably 1 mol/l to 2 mol/l, particularly preferably to about 1.3 mol/l to 1.5 mol/l.
The present invention further relates to the granules of a 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, where 5 10% of the particles have a particle size of < 50 m and 5 10% of the particles have a particle size. of > 400 m, obtained by the process according to the invention described above.
It is particularly preferred for _ 70%, even more preferred ? 80%, of the particles, with preference ? 85% of the particles, of the granules to have a particle size in a range from about 100 m to about 315 m. It is further particularly preferred for _ 50%
of the particles, with preference >_ 55% of the particles, of the granules to have a particle size in a range from about 140 m to about 250 m. As stated above, the apparent volume [volume of the uncompressed product (ml)/100 g of the product] of such granules is preferably in a range from 150 to 180 ml/100 g, with a particularly preferred apparent volume being about 170 ml/100 g.
The present invention additionally relates to the use of the granules, prepared by the process according to the invention, of a hydrohalide of a magnesium-containing complex compound in magnesium therapy and as addition to animal feed. The granules obtained according to the invention of such hydrohalides of the magnesium complex compounds of relevance here are valuable pharmaceuticals and additions to animal feed.
Thus, for example, magnesium L-aspartate hydrochloride is employed for targeted magnesium therapy and also as addition to animal feed and also as mineral supplement for productive livestock. The compounds can be employed in solid granular form or in aqueous solution.
The following examples are indicated in order to explain the invention in more detail without restricting it thereby.
Examples Example 1 Preparation of magnesium L-aspartate hydrochloride 836 kg of L-aspartic acid are added with stirring to 1753 1 of demineralized water. 130 kg of magnesium oxide as powder are added to the resulting dispersion, and the mixture is heated to 60 C with stirring. Then, while stirring, 628 g oz magnesium CnlULlUC 11=ly-1.2-U112-are added, and the mixture is heated with stirring at 60 C for 2 h. The solution is subsequently filtered at 60 C and spray dried with an air inlet temperature of about 320 C and an air outlet temperature of about 1200C with a spraying pressure of about 4 bar in a Niro spray drier.
The final product obtained is a magnesium L-aspartate hydrochloride having the following particle size distribution: < 100 m (6.19%), 100-140 m (19.48%), 140-250 m (57.84%), 250-315 m (10.81%), 315-400 m (4.78%) and 400-500 m (0.90%) . The apparent volume of this final product was 170m1/100 g.
Example 2 Preparation of magnesium L-glutamate hydrochloride 936 1 of demineralized water are heated to 60 C, after which 484 kg of L-glutamic acid are added with stirring. 67 kg of magnesium oxide are added as powder in portions to the resulting dispersion while stirring continuously. The temperature rises, and the solution becomes clear after about 1 h. A solution of 480 kg of magnesium bromide hexahydrate and 384 1 of water (35%
strength solution) is added to this solution. The concentration of the complex is adjusted to 30% by using water. The solution is filtered and then spray dried under the conditions described in Example 1.
This results in magnesium L-glutamate hydrochloride as a white powder in 100% yield.
Example 3 Preparation of calcium L-aspartate hydrochloride 1010 1 of demineralized water are heated to 60 C, after which 509 kg of L-aspartic acid are aaaea Wi111C
stirring. 142 kg of calcium hydroxide are added in the form of a powder in portions to the resulting dispersion while stirring continuously. The temperature rises further and the solution becomes clear after about 1 h. A solution of 281 kg of calcium chloride dihydrate in 325 1 of water (35% strength solution) is added to this solution. The concentration based on the complex is adjusted to 30% with water. This is followed by filtration and spray drying in the manner described iri Example 1.
This results in calcium L-aspartate hydrochloride in the form of a white powder in 100% yield.
Example 4 Preparation of zinc L-aspartate hydrochloride 1025 1 of demineralized water are heated to 60 C, after which 464 kg of L-aspartic acid are added while stirring. 142 kg of zinc oxide in the form of a powder are added in portions to the resulting dispersion with continuous stirring. The temperature rises somewhat, but the solution does not become clear. The temperature is therefore raised to about 90 C, after which a clear solution is obtained. The concentration is adjusted to 30% by adding water.
A solution of 238 kg of zinc chloride in 441 1 of water (35% strength solution) is added to the resulting solution. The concentration based on the complex is adjusted to 30% with water. This is followed by filtration and spray drying in the manner described in Example 1. This results in zinc L-aspartate hydrochloride in the form of a white powder in 100%
yield.
Example 5 Preparation of magnesium L-aspartate hydrochloride 541 kg of L-aspartic acid are dispersed in 1016 1 of demineralized water by stirring with heating to 60 C.
592 kg of a 25% by weight hydrochloric acid and then 164 kg of magnesium oxide as powder are added to this dispersion and stirred. After a clear solution has been obtained, it is filtered and spray dried in the manner described in Example 1, resulting. in magnesium L-aspartate hydrochloride in the form of a white powder in 100% yield.
Example 6 (particle size distribution) The particle size distribution of granular magnesium L-aspartate hydrochloride prepared by the process according to the invention was compared with a finely powdered magnesium L-aspartate hydrochloride prepared by a standard process (disclosed in DE 32 38 118 A1).
The comparative sieve analyses were performed using a Hosokawa Alpine air jet sieve, and the results are shown in Tables 1 and 2 below.12 ~ O O O
b 00 00 N
y~ r1 r-I ~--I
u O O O
Ow O 00 co CN
0 ~ U1 I- O
a a M m in Ln ,r LO
4J O f"1 %D
z O N N
V tIl N ~
H
_ O M a' w O Cl1 b ~ N ~
ro ri O O O O
r-i ro H
a w 00 N
1 O ~
r-I oM O Ln ..~ ~..{
^O o d~ N C9 a ui 0; w ow 0 rn fA co to N
tfl M lfl =
Lfl N r-1 ~
O O
r{
U kO arn v ~4 0 O ~-I N M
z The minimum particle size (dmin) was 0.7 m, tne maximum particle size (dmax)was 260.0 m and the average particle size (d50) was 54.9 m. Figure 1 shows the graphical representation of the particle size distribution of finely powdered magnesium L-aspartate hydrochloride prepared by a standard process disclosed iri DE 32 38 118 Al.
1J ri r~ r~ ri ~-1 r~
a 0 rl ri ri r~ ri r-1 ~ . .
H N m O O O O
a X r-I ri r1 N N N N
m O Q1 ~0 L1l GO ~ al d~
O 0~ Ol 4 M
=
d $4 ZLn V w 14 1-4 O
a~
O m o rn~ ui %D rn-:r 43 O o; rn cf+ r~ ~, a Ln Ln a .r., b ~4 ~Jl O 0 0 0 O 0 0 0 U H
rt W
O
a a, - 00 N O l0 N a0 W
I i O
0 ~- oW O Ol 0~ oD N O~ (7 O
q o cv co O ct+ a0 N N
~ a o 0 O O r N O O 01 fa r~ I- m 01 41 H
N lp N C~ d' d~ O 00 ~
o~ 0 O ~ ~ ~ tfl M O
I0000.O.cØ
N 0 0 N t!1 O O
lfl r-I rl O O
~ u k0 O% rl N M d' Lfl ~
0 0 r=1 N Md' Ltl l0 Il z L, The minimum particle size (amin) was 4ts. u m, UiuC
maximum particle size (d,,,,,.)was 448.7 m and the average particle size (d50) was 250.8 m. Figure 2 shows the graphical representation of the particle size distribution of granular magnesium L-aspartate hydrochloride prepared by the process according to the invention.
Example 7 (flow time and flowability) The flowability of granular magnesium L-aspartate hydrochloride prepared by the process according to the invention was compared with a finely powdered magnesium L-aspartate hydrochloride prepared by a standard process (disclosed in DE 32 38 118 A1). The test arrangement consisted of a conical flow funnel with a height of 22.5 cm, an upper internal diameter of 7.3 cm and a lower internal diameter of 8.2 mm. The test was carried out by the 2.9.16 Method, Ph. Eur., 4th edition, main volume 2002, as follows. 100 g portions of material were put into the funnel. Opening of the funnel orifice was followed by assessment of the flowability, and the time for the whole sample to flow out of the funnel was determined. Two samples were measured in each case. The results are shown in Table 3 below.
Table 3 (flowability) Preparation Standard Standard According According process to the to the invention invention Flowability uneven, uneven, free free not free- not free- flowing flowing flowing flowing Flow time Cannot be cannot be 10 sec 10 sec determined determined Example 8 (dissolving properties) The dissolving properties of granular magnesium L-aspartate hydrochloride prepared by the process according to the invention were compared with a finely powdered magnesium L-aspartate hydrochloride prepared by a standard process (disclosed in DE 32 38 118 A1).
The test arrangement consisted of a glass beaker with stirring bar which was adjusted to 20 revolutions per min. 250 ml of water were introduced and then 10 g of test material were added with the stirrer motor running. The time until dissolution was complete was measured. The results are shown in Table 4 below.
Table 4 (dissolving properties) Preparation Standard Standard According According process to the to the invention invention Dissolving 7 min 7 min 3 min 2 min time Example 9 (water uptake capacity or hygroscopicity) The hygroscopicity of granular magnesium L-aspartate hydrochloride prepared by the process according to the invention was compared with a finely powdered magnesium L-aspartate hydrochloride prepared by a standard process (disclosed in DE 32 38 118 A1). The test arrangement consisted of a desiccator which was adjusted to a relative humidity of 75% with a saturated sodium chloride solution. In each case a defined amount of sample was weighed out and the sample dish was placed in the desiccator. The percentage increase in weight of the weighed amount was determined after 2, 4, 5 and 20 hours. The results are shown in Table S below, from which it is unambiguously evident that the hygroscopicity of the granules according to the invention is distinctly reducect comparea wirn a 1111e1y powdered product according to the prior art. Figure 3 shows a graphical representation of the measurements shown in Table 5.
Table 5 (hygroscopicity) Testing Standard Standard According According time to the to the invention invention 2 h 0.35 0.30 0.18 0.16 4 h 0.63 0.55 0.33 0.30 5 h 0.72 0.71 0.43 0.40 20 h 3.06 2.70 1.74 1.63
Claims (16)
1. Granules of a 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, wherein <= 10% of the particles have a particle size of <
50 µm and <= 10% of the particles have a particle size of > 400 µm.
50 µm and <= 10% of the particles have a particle size of > 400 µm.
2. The granules according to Claim 1, wherein >= 70% of the particles have a particle size in a range from about 100 µm to about 315 µm.
3. The granules according to claim 1 wherein >= 80% of the particles have a particle size in a range from about 100 µm to about 315 µm.
4. The granules according to Claim 1, wherein >= 50% of the particles have a particle size in a range from about 140 µm to about 250 µm.
5. A 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.
(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.
6. The process according to Claim 5, wherein 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.
7. Process according to Claim 5 or 6, wherein 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.
8. The process according to Claims 5, 6 or 7 wherein 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.
in which M2+ is a divalent metal cation, Hal is a halide ion, n is 1 or 2 and m is 0 to 10.
9. The process according to Claims 5, 6, 7 or 8, wherein the amino dicarboxylic acid is L-glutamic acid or L-aspartic acid.
10. The process according to any one of Claims 5 to 9, wherein the divalent metal (M) is an alkaline earth metal or a heavy metal.
11. The process according to any one of Claims 5 to 10, wherein the hydrohalide of the complex compound is an alkaline earth metal L-aspartate hydrohalide or an alkaline earth metal L-glutamate hydrohalide.
12. The process according to any one of Claims 5 to 11, wherein the hydrohalide of the complex compound is magnesium L-aspartate hydrochloride or magnesium L-glutamate hydrochloride.
13. The process according to any one of claims 5 to 12, wherein the concentration of the hydrohalide of the complex compound in the aqueous solution in step (a) is set at from 0.5 mol/l to 3 mol/l.
14. A 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, by reacting an amino dicarboxylic acid with a hydroxide, oxide and/or carbonate of the metal (M) in aqueous solution or suspension with a halide of the metal (M) and/or hydrohalic acid;
(b) spray drying of the aqueous solution obtained in step (a) at a 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, and wherein 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.
(a) preparation of an aqueous solution of the hydrohalide of the complex compound, by reacting an amino dicarboxylic acid with a hydroxide, oxide and/or carbonate of the metal (M) in aqueous solution or suspension with a halide of the metal (M) and/or hydrohalic acid;
(b) spray drying of the aqueous solution obtained in step (a) at a 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, and wherein 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.
15. The process according to Claim 14, wherein 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.
in which M2+ is a divalent metal cation, Hal- is a halide ion, n is 1 or 2 and m is 0 to 10.
16. Use of granules, prepared by the process of any one of claims 5 to 15 of a hydrohalide of a magnesium-containing complex compound or of the granules, defined in Claims 1, 2, or 3 of a hydrohalide of a magnesium-containing complex compound in magnesium therapy and as addition to animal feed.
Applications Claiming Priority (2)
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EP04019858.2-1211 | 2004-08-20 | ||
EP04019858A EP1627879B1 (en) | 2004-08-20 | 2004-08-20 | Process for preparing hydrohalogen metal complexes of specific particle size |
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CA2516147A1 CA2516147A1 (en) | 2006-02-20 |
CA2516147C true CA2516147C (en) | 2009-12-29 |
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CA002516147A Active CA2516147C (en) | 2004-08-20 | 2005-08-17 | Process for preparing certain hydrohalide metal complex compounds having a specific coarse structure |
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EP (1) | EP1627879B1 (en) |
AT (1) | ATE342905T1 (en) |
AU (1) | AU2005203592B2 (en) |
CA (1) | CA2516147C (en) |
DE (1) | DE502004001816D1 (en) |
HK (1) | HK1083849A1 (en) |
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CN102875402B (en) * | 2012-10-30 | 2015-06-24 | 宜兴市前成生物有限公司 | Method for preparing magnesium L-aspartate |
CN106883135A (en) * | 2015-12-16 | 2017-06-23 | 辽宁药联制药有限公司 | A kind of method for preparing MAH bulk drug |
Family Cites Families (2)
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DE2228101C3 (en) * | 1972-06-09 | 1979-07-05 | Verla-Pharm. Arzneimittelfabrik, Apotheker H.J. V. Ehrlich, Gmbh & Co Kg, 8132 Tutzing | Process for the production of complex compounds from aminodicarboxylic acid ions, magnesium ions and halide ions |
DE3238118A1 (en) * | 1982-10-14 | 1984-04-19 | Verla-Pharm, Arzneimittelfabrik Apotheker H.J. v. Ehrlich GmbH & Co KG, 8132 Tutzing | METHOD FOR PRODUCING COMPLEX COMPOUNDS FROM AMINODICARBONIC ACIDS, DUAL VALUE METALIONS AND HALOGENIDIONS |
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2004
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- 2004-08-20 DE DE502004001816T patent/DE502004001816D1/en active Active
- 2004-08-20 AT AT04019858T patent/ATE342905T1/en active
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PT1627879E (en) | 2006-12-29 |
HK1083849A1 (en) | 2006-07-14 |
CA2516147A1 (en) | 2006-02-20 |
NZ541845A (en) | 2007-01-26 |
DE502004001816D1 (en) | 2006-11-30 |
EP1627879B1 (en) | 2006-10-18 |
EP1627879A1 (en) | 2006-02-22 |
ATE342905T1 (en) | 2006-11-15 |
AU2005203592B2 (en) | 2010-07-22 |
AU2005203592A1 (en) | 2006-03-09 |
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