Ammonium ferric citrate organic acid compound as well as preparation method and application thereof

Abstract

The invention relates to an ammonium ferric citrate organic acid compound or a salt thereof and a preparation method thereof, and also relates to a composition containing the ammonium ferric citrate organic acid compound or the salt thereof and application of the compound as an animal feed additive and a food additive. The invention also relates to application of the ammonium ferric citrate organic acid compound or the salt thereof in preparation of medicines for preventing and treating diarrhea of bred animals.

Description

Technical field:

[0001] The invention relates to an ammonium ferric citrate organic acid complex or its salt and a preparation method thereof, further relates to a composition comprising the ammonium ferric citrate organic acid complex or its salt and application of the complex as an animal feed additive and a food additive, and further relates to application of the ammonium ferric citrate organic acid complex or its salt in preparing a medicament for preventing and treating diarrhea in farmed animals. Background technology:

[0002] Ammonium ferric citrate, also known as ammonium ferric citrate and 2-hydroxy-1,2,3-propanetricarboxylic acid ferric ammonium salt, is a complex salt of ferric citrate and ammonium citrate. It is an organic non-hemoglobin iron complex or iron salt composed of naturally occurring substances (iron, citric acid and ammonia), and plays an important role in the fields of food and animal husbandry.

[0003] In food or medicine, ammonium ferric citrate is used as an iron source for the treatment of iron deficiency, as a food additive for fortifying the nutrition of bread or dietary iron supplements, and as an anti-caking agent in products containing compound sweeteners and in the production of table salt.

[0004] In the field of animal husbandry, ammonium ferric citrate is used to alleviate the production of H2S in the rumen, and is used as a nutrient in health products for dogs and cats to promote their growth, supplement various trace elements and vitamins required for their growth, beautify their fur, enhance the body's immune function, balance nutrition, regulate estrus, increase the number of fetuses, and promote reproductive system health. It is also used as a compound mineral additive in poultry feed to supplement the poultry's need for mineral elements and promote poultry growth and development.

[0005] However, as described in CN113234107A, ammonium ferric citrate is very easy to deliquesce and deteriorate when exposed to light, and needs to be stored away from light and at low temperatures. Direct application in products such as food, feed or medicine will lead to problems such as unstable product quality, easy moisture absorption, and easy deterioration, and cannot meet the actual application in the field of animal breeding. Summary of the invention:

[0006] In order to solve the technical problems that ammonium ferric citrate is very easy to deliquesce, easily deteriorates when exposed to light, and needs to be stored away from light and at low temperature, the present invention provides an ammonium ferric citrate organic acid complex or a salt thereof which is not easy to deteriorate by moisture absorption and has improved stability.

[0007] The invention also provides a method for preparing the ammonium ferric citrate organic acid complex or its salt.

[0008] The present invention also provides a feed composition, a food composition and a medicinal composition comprising the ammonium ferric citrate organic acid complex or its salt.

[0009] The invention also provides the use of the ammonium ferric citrate organic acid complex or its salt as or in the preparation of an animal feed additive or a food additive.

[0010] The present invention also provides the use of the ammonium ferric citrate organic acid complex or its salt in the preparation of medicines for preventing and treating animal diarrhea.

[0011] In order to achieve the above-mentioned purpose of the present invention, the following technical solutions are particularly adopted:

[0012] The invention provides an ammonium ferric citrate organic acid complex comprising ammonium ferric citrate and an organic acid and a salt thereof.

[0013] In some technical solutions, the ammonium ferric citrate-organic acid complex or its salt further comprises at least one solvent that can solvate the ammonium ferric citrate and the organic acid.

[0014] On the other hand, the present invention also provides a method for preparing the above-mentioned ammonium ferric citrate organic acid complex or its salt, comprising the following steps:

[0015] (1) dissolving an organic acid or a salt thereof in a solvent to obtain an organic acid or a salt thereof solution;

[0016] (2) dissolving ammonium ferric citrate in a solvent to obtain an ammonium ferric citrate solution;

[0017] (3) adding the ammonium ferric citrate solution to the organic acid or its salt solution to obtain a reaction solution, and stirring at a reaction or heating temperature of 25-60° C. for 1-4 hours;

[0018] (4) stirring the reaction solution after step (3) at room temperature for 4-15 hours;

[0019] (5) filtering the reaction solution after step (4), and concentrating and drying the filtrate to obtain an ammonium ferric citrate organic acid complex or a salt thereof containing ammonium ferric citrate and an organic acid.

[0020] The present invention also provides a composition, which comprises the above-mentioned ammonium ferric citrate organic acid complex or its salt; preferably, the composition is used as a medicine, feed, or food.

[0021] The present invention also provides a feed composition, which comprises the above-mentioned ammonium ferric citrate organic acid complex or its salt, and one or more carriers, excipients, diluents and solvents acceptable to feed.

[0022] The present invention also provides a food composition, which comprises the above-mentioned ammonium ferric citrate organic acid complex or its salt, and nutritionally acceptable auxiliary materials.

[0023] The present invention also provides a pharmaceutical composition, which comprises the above-mentioned ammonium ferric citrate organic acid complex or its salt, and pharmaceutically acceptable excipients.

[0024] The present invention also provides the use of the ammonium ferric citrate organic acid complex or its salt as or in the preparation of an animal feed additive.

[0025] The present invention also provides the use of the ammonium ferric citrate organic acid complex or its salt as or in the preparation of food additives.

[0026] The present invention also provides the use of the ammonium ferric citrate organic acid complex in the preparation of a medicine for preventing and treating animal diarrhea.

[0027] The invention also provides the above-mentioned ammonium ferric citrate organic acid complex, which is used as a medicine for preventing and treating animal diarrhea.

[0028] The present invention also provides a method for preventing and treating diarrhea in animals, comprising administering the ammonium ferric citrate organic acid complex to the animals.

[0029] Compared with ammonium ferric citrate, the ammonium ferric citrate organic acid complex or its salt provided by the present invention has the beneficial technical effects of stable appearance, significantly improved or enhanced moisture absorption, and significantly improved stability under light. Animal breeding experiments further show that the ammonium ferric citrate organic acid complex or its salt has a breeding effect comparable to or even better than that of ammonium ferric citrate, and can be used as an upgraded product to replace ammonium ferric citrate.

[0030] Any embodiment of any aspect of the present invention can be combined with other embodiments, as long as there is no contradiction between them. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the technical feature in other embodiments, as long as there is no contradiction between them. Description of the drawings:

[0031] Figure 1 This is the FTIR spectrum of ammonium ferric citrate organic acid complex A.

[0032] Figure 2 This is a comparison chart of the FTIR spectra of ammonium ferric citrate organic acid complex B and ammonium ferric citrate and fumaric acid raw materials.

[0033] Figure 3 This is the FTIR spectrum of ammonium ferric citrate organic acid complex C.

[0034] Figure 4 This is the XRD pattern of ammonium ferric citrate organic acid complex A.

[0035] Figure 5 This is the XRD pattern of ammonium ferric citrate organic acid complex B.

[0036] Figure 6 This is the XRD pattern of ammonium ferric citrate raw material.

[0037] Figure 7 This is the XRD pattern of fumaric acid raw material.

[0038] Figure 8 This is the XRD pattern of ammonium ferric citrate organic acid complex C.

[0039] Fig. 9 It is the FTIR spectrum of the raw material mixture of ammonium ferric citrate and fumaric acid with a molar ratio of 2:1.

[0040] Fig.10 It is the XRD spectrum of the raw material mixture of ammonium ferric citrate and fumaric acid in a molar ratio of 2:1.

[0041] Fig.11 It is the DSC curve of ammonium ferric citrate raw material.

[0042] Fig.12 It is the DSC curve of ammonium ferric citrate organic acid complex B.

[0043] Fig.13 It is the DSC curve diagram of fumaric acid raw material.

[0044] Fig.14 It is the DSC curve of the raw material mixture of ammonium ferric citrate and fumaric acid with a molar ratio of 2:1.

[0045] The above contents are only an overview of certain aspects of the present invention, but are not limited to these aspects. The above contents and other aspects will be described in more detail and complete below.

[0046] Detailed description of the invention:

[0047] The following detailed description is intended to enable those skilled in the art to implement different embodiments. The description of specific devices, technologies or applications is only an example. The present invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are included in the scope of the present invention as defined in the claims. In addition, certain technical features of the present invention are described separately in multiple independent embodiments for clarity, but can also be provided in a single embodiment in combination or in any suitable sub-combination.

[0048] Ammonium ferric citrate organic acid complex disclosed by the present invention

[0049] The invention provides an ammonium ferric citrate organic acid complex and a salt thereof.

[0050] Wherein, the organic acid is an organic acid or acidic amino acid acceptable to medicine, food and feed, the organic acid is selected from fumaric acid, maleic acid, succinic acid, malonic acid, oxalic acid, benzoic acid or sorbic acid, and the acidic amino acid is selected from glutamic acid or aspartic acid; preferably, the organic acid is fumaric acid or maleic acid.

[0051] In some specific embodiments, at least one solvent capable of solvating ammonium ferric citrate and an organic acid is further included; preferably, the solvent is selected from water, methanol, ethanol, methanol-water solution or ethanol-water solution.

[0052] In some specific embodiments, the salt of the ammonium ferric citrate organic acid complex is selected from a sodium salt, a potassium salt or an ammonium salt; preferably, the salt of the ammonium ferric citrate organic acid complex is an ammonium ferric citrate organic acid complex sodium salt.

[0053] In some specific embodiments, the ammonium ferric citrate organic acid complex or its salt is used as a medicine, feed, or food; preferably, the ammonium ferric citrate organic acid complex or its salt is used as a medicine for preventing and treating diarrhea in animals.

[0054] The "acidic amino acid" refers to an amino acid containing one amino group and two carboxyl groups, with an isoelectric point between about 2.8 and 3.2.

[0055] The term "pharmaceutically, food and feed acceptable" means that the substance or composition must be suitable chemically or toxicologically for use as a drug, food or feed.

[0056] The term “comprising” described in the present invention is an open expression, which includes the contents explicitly mentioned in the present invention but does not exclude other contents.

[0057] A method for preparing the ammonium ferric citrate organic acid complex comprises the following steps:

[0058] (1) dissolving an organic acid in a solvent to obtain an organic acid solution;

[0059] (2) dissolving ammonium ferric citrate in a solvent to obtain an ammonium ferric citrate solution;

[0060] (3) adding the ammonium ferric citrate solution to the organic acid solution to obtain a reaction solution, and stirring at 25-60° C. for 1-4 hours;

[0061] (4) stirring the reaction solution after step (3) at room temperature for 4-15 hours;

[0062] (5) filtering the reaction solution after step (4), concentrating and drying the filtrate to obtain an ammonium ferric citrate-organic acid complex containing ammonium ferric citrate and an organic acid.

[0063] Wherein, the organic acid is an organic acid or an acidic amino acid acceptable to medicine, food and feed, the organic acid is selected from fumaric acid, maleic acid, succinic acid, malonic acid, oxalic acid, benzoic acid or sorbic acid, and the acidic amino acid is selected from glutamic acid or aspartic acid; the solvent described in step (1) and step (2) is a solvent that can solvate ammonium ferric citrate and the organic acid, and is selected from water, methanol, ethanol, methanol aqueous solution or ethanol aqueous solution.

[0064] In some specific embodiments, the molar ratio of ammonium ferric citrate and the organic acid in the preparation method is 1:1-3:1; preferably, the molar ratio of ammonium ferric citrate and the organic acid is 2:1; more preferably, the organic acid is fumaric acid or maleic acid.

[0065] In some specific embodiments, in order to obtain an ammonium ferric citrate organic acid complex or its salt with higher chemical purity and lower impurity content, the preparation of the ammonium ferric citrate organic acid complex or its salt provided by the present invention further comprises: concentrating and drying the filtrate obtained in step (5) of the above preparation method to obtain an ammonium ferric citrate organic acid complex containing ammonium ferric citrate and an organic acid, and placing it in methanol, ethanol, methanol aqueous solution or ethanol aqueous solution for pulping treatment, in order to further remove impurities.

[0066] In some embodiments, in order to improve the solubility of the ammonium ferric citrate organic acid complex or its effective utilization in the organism, it is salted by chemical synthesis. A method for preparing the salt of the ammonium ferric citrate organic acid complex comprises the following steps:

[0067] (1) dissolving an organic acid salt in a solvent to obtain an organic acid salt solution;

[0068] (2) dissolving ammonium ferric citrate in a solvent to obtain an ammonium ferric citrate solution;

[0069] (3) adding the ammonium ferric citrate solution to the organic acid salt solution to obtain a reaction solution, and stirring the mixture under heating for 1 to 4 hours;

[0070] (4) stirring the reaction solution after step (3) at room temperature for 4-15 hours;

[0071] (5) filtering the reaction solution after step (4), concentrating and drying the filtrate to obtain a salt of ammonium ferric citrate organic acid complex containing ammonium ferric citrate and an organic acid salt.

[0072] Wherein, the organic acid salt is an organic acid salt or an acidic amino acid salt acceptable for pharmacy, food and feed, the organic acid is selected from fumaric acid, maleic acid, succinic acid, malonic acid, oxalic acid, benzoic acid or sorbic acid, and the acidic amino acid is selected from glutamic acid, aspartic acid or γ-aminobutyric acid; the solvent used in step (1) and step (2) is a solvent that can solvate ammonium ferric citrate and the organic acid salt, independently selected from water, methanol, ethanol, methanol aqueous solution or ethanol aqueous solution. Preferably, the heating condition is 25-60°C.

[0073] In some specific embodiments, the organic acid salt is an organic acid sodium salt, and the product obtained by the preparation method of the salt of the ammonium ferric citrate organic acid complex is an ammonium ferric citrate organic acid complex sodium salt, and the molar ratio of sodium ions to organic acid in the organic acid sodium salt is 1: 1-1: 2. For example, taking fumaric acid as an example, it can include monosodium fumarate and disodium fumarate.

[0074] In some embodiments, the ammonium ferric citrate organic acid complex and its salt obtained by the above preparation method further comprises at least one solvent that can solvate the ammonium ferric citrate and the organic acid and its salt, and the solvent is selected from: water, methanol, ethanol, or a combination thereof.

[0075] In some embodiments, the ammonium ferric citrate-organic acid complex provided by the present invention, wherein the organic acid is selected from: fumaric acid or maleic acid.

[0076] Fumaric acid is fumaric acid. Maleic acid is maleic acid, which has the same molecular formula, molecular weight and the same number of carboxyl groups as fumaric acid, and can be used as a substitute for fumaric acid in the preparation of ammonium ferric citrate organic acid complex.

[0077] In some embodiments, the solvent that can solvate ammonium ferric citrate and the organic acid is selected from: water.

[0078] In a specific embodiment, the ammonium ferric citrate organic acid complex provided by the present invention comprises ammonium ferric citrate and fumaric acid, and the preparation method thereof comprises the following steps:

[0079] (1) dissolving fumaric acid in water to obtain a fumaric acid solution;

[0080] (2) dissolving ammonium ferric citrate in water to obtain an ammonium ferric citrate solution;

[0081] (3) adding the ammonium ferric citrate solution to the fumaric acid solution to obtain a reaction solution, and stirring at 50° C. for 1-4 hours;

[0082] (4) stirring the reaction solution after step (3) at room temperature for 4-15 hours;

[0083] (5) filtering the reaction solution after step (4), concentrating and drying the filtrate to obtain an ammonium ferric citrate fumaric acid complex containing ammonium ferric citrate and fumaric acid.

[0084] In some embodiments, in the preparation method of the above-mentioned ammonium ferric citrate fumaric acid complex, the molar ratio of ammonium ferric citrate and fumaric acid is 1:1 to 3:1, and the element content of the provided ammonium ferric citrate fumaric acid complex is C23.8-25.82%, H 4.09-4.29%, N5.74-6.19%, O 45.12-48.84%, and Fe16.13-18.8%.

[0085] Furthermore, the ammonium ferric citrate fumarate complex provided by the present invention also contains a certain amount of water.

[0086] In a specific embodiment, in the preparation method of the above-mentioned ammonium ferric citrate fumaric acid complex, the molar ratio of ammonium ferric citrate and fumaric acid is 2:1, and the element content of the provided ammonium ferric citrate fumaric acid complex is C25.82%, H 4.09%, N 6.19%, and Fe 18.8%.

[0087] In some preparation schemes, the ammonium ferric citrate sodium fumarate provided by the present invention is prepared by the above method, and the process involved in step (1) in the above preparation method is to dissolve the sodium fumarate in water to obtain a sodium fumarate solution.

[0088] In some specific preparation schemes, the sodium fumarate salt is monosodium fumarate, and the ammonium ferric citrate fumarate complex salt is ammonium ferric citrate fumarate monosodium salt.

[0089] In some specific preparation schemes, the sodium fumarate salt is disodium fumarate salt, and the ammonium ferric citrate fumarate complex salt is disodium ammonium ferric citrate fumarate salt.

[0090] The characterization method of the ammonium ferric citrate organic acid complex and its salt provided by the present invention includes but is not limited to: elemental analysis, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and differential scanning calorimetry (DSC).

[0091] Elemental analysis : The elemental analysis results were collected in the Elementar Vario EL Cube elemental analyzer, with the combustion furnace temperature at 950 °C and the reduction furnace temperature at 600 °C. The reference for data analysis is JY / T 0580-2020 General Rules for Elemental Analyzer Analysis Methods.

[0092] Fourier Transform Infrared Spectroscopy (FTIR) : FTIR spectra were collected in a Fourier transform infrared spectrometer model FT-IR NICOLET 6700, with an absorption wavelength of 400-4000cm-1 The test method is potassium bromide tableting, and the detection basis is GB / T 6040-2019 General rules for infrared spectroscopy analysis methods.

[0093] X-ray diffraction (XRD) :XRD patterns were collected in an Empyrean X-ray diffractometer. The detection conditions were: Cu target Kɑ radiation, the voltage and current of the X-ray tube were 40 kV and 40 mA, respectively, the divergence slit was 1 / 8°, the anti-scattering slit measurement step was 1 / 4°, the anti-scattering slit was 7.5 mm, the step length was 0.02°2θ, the measurement angle range was from 0°2θ to 90°2θ, and the dwell time for each step was 40 s. The detection was based on the 0451 X-ray diffraction method of Part IV of the 2020 edition of the Pharmacopoeia of the People's Republic of China.

[0094] Differential Scanning Calorimetry (DSC) :DSC data were collected on a DSC214 differential scanning calorimeter from NETZSCH, Germany. 0.5-5 mg of sample was placed in a pinhole aluminum pan, purged with dry nitrogen at 40 mL / min, and heated from room temperature to 180°C at a rate of 10°C / min. The test was based on JY / T 0589.3-2020 General Rules for Thermal Analysis Methods Part 3 Differential Scanning Calorimetry.

[0095] The physicochemical property stability research test of the organic acid complex containing ammonium ferric citrate provided by the present invention includes a high humidity stability test and a light stability test.

[0096] High humidity stability test : The samples were placed in a culture dish, spread into a thin layer of ≤5 mm, and placed in a high humidity environment of 25°C and 75±5%RH. Samples were taken for testing on the 5th and 10th days, and each sample was sampled twice in parallel.

[0097] Light stability test : The sample was placed in a culture dish, spread into a thin layer of ≤5mm, placed in a light environment of 4500Lx±500Lx, and samples were taken for testing on the 0th, 5th and 10th days. Each sample was sampled twice in parallel.

[0098] Compared with ammonium ferric citrate, the ammonium ferric citrate organic acid complex or its salt provided by the present invention has the beneficial technical effects of significantly improving the appearance stability, significantly improving or increasing the moisture absorption under room temperature and high humidity conditions, and significantly improving the chemical property stability under light conditions.

[0099] The bioavailability research test of the ammonium ferric citrate organic acid complex provided by the present invention includes the effect test of the complex and its salt on the growth performance and diarrhea of ​​piglets, the effect test on the growth performance of broiler chickens, and the application effect research test in duck feed. The research results fully show that the ammonium ferric citrate organic acid complex and its salt can be used in the breeding of pigs, chickens and ducks, and can improve the growth performance of pigs, chickens and ducks. It has a breeding effect comparable to or even better than ammonium ferric citrate, can effectively improve the growth performance or production performance of animals, and can be used as an upgraded product to replace ammonium ferric citrate.

[0100] Application of the ammonium ferric citrate organic acid complex of the present invention

[0101] In food, ammonium ferric citrate can be used as: (1) an iron source for the treatment of iron deficiency; (2) a food additive for the nutritional enhancement of bread; (3) a dietary iron supplement; (4) an anti-caking agent in products containing compound sweeteners and in the production of salt. Ammonium ferric citrate can also be used to prevent or treat intestinal microbial imbalance caused by iron in the human body, including controlling the growth of pathogenic bacteria such as Escherichia coli, Enterobacter bacteria and Streptococcus pneumoniae, or to prevent or treat intestinal functional disorders, including diarrhea, enteritis or intestinal infection.

[0102] In the field of animal husbandry: ammonium ferric citrate can be used to alleviate the production of H2S in the rumen; as a nutrient, ammonium ferric citrate can also be used in health products for dogs and cats to promote the growth of dogs and cats, supplement various trace elements and vitamins required for their growth, beautify their fur, enhance the body's immune function, balance nutrition, regulate estrus, increase the number of fetuses, and promote the health of the reproductive system. It can also be used as a composite mineral additive in poultry feed to supplement the poultry's need for mineral elements and promote poultry growth and development.

[0103] The results of the bioavailability research test of the organic acid complex of ammonium ferric citrate and its salt provided by the present invention show that the organic acid complex of ammonium ferric citrate and its salt have a breeding effect comparable to or even better than that of ammonium ferric citrate in animal experiments. The organic acid complex of ammonium ferric citrate and its salt improve its stability in feed, food and medicine due to its hygroscopicity mitigation, reduce the reaction with other ingredients so as not to reduce the content of other nutrients or formula active ingredients coexisting with it, and its effectiveness in animals can replace ammonium ferric citrate in feed, food and medicine. Therefore, the uses of ammonium ferric citrate mentioned and not mentioned in the above content are deemed to be within the scope of protection of the claims of the present invention.

[0104] The present invention provides the use of the ammonium ferric citrate organic acid complex and / or its salt as or in the preparation of a feed additive, and the feed additive is suitable for animals at various growth stages.

[0105] The animal can be selected from livestock, poultry, aquaculture animals or pets at various growth stages.

[0106] Furthermore, the livestock include but are not limited to: pigs, cattle, sheep, horses, rabbits, minks or donkeys, the poultry include but are not limited to: chickens, turkeys, ducks, geese, quails or pigeons, the aquaculture animals include but are not limited to: fish, shrimps, turtles, crabs, tortoises, bullfrogs, eels or loaches, and the pets include but are not limited to: dogs or cats of various subspecies.

[0107] In one embodiment, the ammonium ferric citrate organic acid complex and / or its salt is used as or in the preparation of an iron supplement. Preferably, the ammonium ferric citrate organic acid complex and / or its salt is: ammonium ferric citrate fumaric acid complex and / or its sodium salt.

[0108] In one embodiment, ammonium ferric citrate organic acid complex and / or its salt is used to alleviate H2S production in the rumen.

[0109] In one embodiment, the ammonium ferric citrate organic acid complex and / or its salt is used as or in the preparation of an animal feed additive. Further, the animal feed additive is used in animal breeding to promote animal growth; the feed additive is selected from animal iron supplements and / or animal growth promoters.

[0110] In one embodiment, the ammonium ferric citrate organic acid complex and / or its salt is used as or in the preparation of a health product for dogs and cats, wherein the health product for dogs and cats promotes the growth of dogs and cats. Preferably, the ammonium ferric citrate organic acid complex and / or its salt is used as a nutrient.

[0111] In one embodiment, the ammonium ferric citrate organic acid complex and / or its salt is used as or in the preparation of nursery feed. Further, the nursery feed can reduce the diarrhea rate of weaned pigs, increase the feed intake of weaned pigs, and reduce the feed conversion rate, thereby increasing the growth rate of weaned pigs, increasing feed compensation, and promoting the growth of weaned pigs.

[0112] In another embodiment, the ammonium ferric citrate organic acid complex and / or its salt is used as or in the preparation of broiler feed. Further, the broiler feed can increase the feed intake of broilers, reduce the feed-to-meat ratio, and improve the feed conversion rate, thereby effectively promoting the growth of broilers.

[0113] In another embodiment, the ammonium ferric citrate organic acid complex and its salt are used as or in the preparation of duck feed. Further, the duck feed can increase the feed intake of ducks and reduce the feed-to-meat ratio, that is, improve the feed conversion rate, thereby promoting the growth of ducks by increasing the feeding of ducks and improving feed conversion.

[0114] The present invention provides the use of the ammonium ferric citrate organic acid complex and / or its salt as or in the preparation of a food additive; preferably, the food additive is a food iron fortifier.

[0115] In one embodiment, the ammonium ferric citrate organic acid complex and / or its salt is used as or in the preparation of an iron source for use in a drug for treating diseases caused by iron deficiency.

[0116] In one embodiment, the ammonium ferric citrate organic acid complex and / or its salt is used as an iron source for treating iron deficiency diseases.

[0117] In one embodiment, a method for treating an iron deficiency disease comprises administering an ammonium ferric citrate organic acid complex and / or a salt thereof to an animal.

[0118] In one embodiment, the ammonium ferric citrate organic acid complex and / or its salt is used in the preparation of bread. Further, the ammonium ferric citrate organic acid complex and / or its salt is used to strengthen the nutrition of bread.

[0119] In one embodiment, the ammonium ferric citrate organic acid complex and / or its salt is used in the preparation of a dietary iron supplement.

[0120] In one embodiment, the ammonium ferric citrate organic acid complex and / or its salt is used as an anti-caking agent in the production of products containing compound sweeteners and table salt.

[0121] The bioavailability study test results of the organic acid complex containing ammonium ferric citrate and / or its salt provided by the present invention show that the organic acid complex containing ammonium ferric citrate and / or its salt has the effect of improving diarrhea in weaned pigs similar to that of ammonium ferric citrate.

[0122] Thus, in one embodiment, the ammonium ferric citrate organic acid complex and / or its salt is used to prevent or treat intestinal microbial imbalance caused by iron in the human body, including controlling the growth of pathogenic bacteria such as Escherichia coli, Enterobacter bacteria and Streptococcus pneumoniae, or to prevent or treat intestinal functional disorders, including diarrhea, enteritis or intestinal infection, or as an effective ingredient for preparing drugs for preventing and treating diarrhea in humans or animals.

[0123] A method for raising animals, comprising administering the aforementioned ammonium ferric citrate organic acid complex and / or its salt, or the aforementioned composition comprising the ammonium ferric citrate organic acid complex and / or its salt to the animals.

[0124] Compositions of the present invention

[0125] Based on the use of ammonium ferric citrate organic acid complex and / or its salt as or in the preparation of feed additives, food additives and medicines, the present invention provides a composition comprising the ammonium ferric citrate organic acid complex and / or its salt, and the composition includes a feed composition, a food composition and a pharmaceutical composition.

[0126] The "composition" of the present invention refers to a group or collection containing one or more compounds provided by the present invention.

[0127] The present invention provides a composition comprising the above-mentioned ammonium ferric citrate organic acid complex or its salt; preferably, the composition is used as a medicine, feed, or food.

[0128] The present invention provides a feeding composition, comprising the above-mentioned ammonium ferric citrate organic acid complex and / or its salt, and one or more of a carrier, an excipient, a diluent and a solvent acceptable to feed.

[0129] The "carrier" involved in the present invention refers to a feedable material that can carry active ingredients, improve their dispersibility, and has good chemical stability and adsorption, and can be selected from: organic carriers and inorganic carriers. The organic carrier is a material containing a lot of crude fiber, including but not limited to: corn flour, corn cob flour, wheat bran, rice husk powder, defatted rice bran, bran, corn stalk powder, peanut shell powder, etc. The inorganic carrier is selected from: minerals, preferably, selected from: calcium salts and silicon oxides, used for the preparation of trace element premixes, including but not limited to: calcium carbonate, silicates, vermiculite, zeolite, sepiolite, etc.

[0130] The "diluent" referred to in the present invention refers to a substance that evenly distributes the additive raw material in the material, dilutes the high-concentration additive raw material into a low-concentration premix or premix, can separate trace components from each other, reduce the mutual reaction between active components, increase the stability of active components but do not affect the physicochemical properties of related substances, and is selected from: organic diluents and inorganic diluents. Organic diluents include but are not limited to: corn flour, degermed corn flour, dextrose (glucose), sucrose, coarse wheat flour with bran, fried soybean flour, wheat flour, corn protein powder, etc.; inorganic diluents include but are not limited to: limestone, monocalcium phosphate, shell powder, kaolin (white clay), salt and sodium sulfate.

[0131] The "excipients" involved in the present invention are wetting agents that induce the inherent viscosity of the substance itself, adhesives that make the substance stick together, disintegrants that break the whole sheet of the substance into many fine particles, retention agents that reduce the friction between particles or anti-sticking agents that prevent the material from sticking, including but not limited to: magnesium stearate, talc, vegetable oil, magnesium lauryl sulfate, starch, starch slurry, water, inorganic salts, dextrin, powdered sugar, etc.

[0132] The "solvent" referred to in the present invention refers to the solvent required to dissolve or disperse a solid, including but not limited to: water, ethanol, glycerol, etc.

[0133] In some embodiments, the composition further comprises: additional animal feed additives and / or animal feed raw materials.

[0134] The "feed additives" referred to in the present invention refer to small or trace substances added during feed processing, production and use, including nutritional feed additives and / or general feed additives.

[0135] The "animal" referred to in the present invention refers to a person or farmed animal that cannot convert inorganic matter into organic matter and can only use organic matter as food to carry out life activities such as eating, digestion, absorption, breathing, circulation, excretion, sensation, movement and reproduction. "Farmed animals" include poultry, livestock, aquaculture animals and other animals that are legally captured by artificial breeding, including pets, such as cats and dogs. The "livestock" is, for example, any one of pigs, cattle, horses, goats, sheep, deer and many useful rodents. The "poultry" includes, for example, chickens, ducks, geese, quails, pigeons, etc. The "aquaculture animals" include, for example, fish, shrimps, turtles, tortoises, etc.

[0136] The "feed" referred to in the present invention refers to an industrially processed and manufactured product for animal consumption. Unless otherwise specified, the "feed" or "animal feed" comprises animal feed raw materials and one or more animal feed additives.

[0137] The "nutritional feed additives" referred to in the present invention refer to small or trace substances added to compound feed to balance feed nutrients, improve feed utilization, and directly exert nutritional effects on animals, selected from: amino acids, amino acid salts and analogs, vitamins and vitamin-like substances, mineral elements and their complexes (chelates), microbial enzyme preparations or non-protein nitrogen.

[0138] The "general feed additives" involved in the present invention are also called "non-nutritional additives", which refer to some non-nutritional substances added to feed to improve feed utilization, ensure feed quality and quality, and be beneficial to animal health or metabolism, including: growth promoters, anthelmintics and health care agents, flavoring and attractants, feed conditioners, feed modulators, feed storage agents and Chinese herbal medicine additives.

[0139] The "animal feed raw materials" involved in the present invention are selected from: cereals and their processed products, oil seeds and their processed products, leguminous crop seeds and their processed products, tubers, roots and their processed products, other seeds, fruit products and their processed products, forage, roughage and their processed products, other plants, algae and their processed products, dairy products and their by-products, terrestrial animal products and their by-products, fish, other aquatic organisms and their by-products, minerals, microbial fermentation products and by-products, other feed raw materials and other feeding substances, etc.

[0140] The present invention provides a food composition, comprising the above-mentioned ammonium ferric citrate organic acid complex and / or its salt, and nutritionally acceptable auxiliary materials. Preferably, the auxiliary materials are selected from: nutritionally acceptable inert carriers, anti-wetting agents, antioxidants, wetting agents, thickeners, stabilizers, multivalent sequestrants, lubricants, preservatives, sweeteners and acidity regulators or combinations thereof. Preferably, the carrier includes but is not limited to: maltodextrin, starch, calcium sulfate, magnesium sulfate, calcium carbonate, cellulose derivatives, lactose and its derivatives or any mixture of such carriers and other analogs. Preferably, the above-mentioned ammonium ferric citrate organic acid complex and / or its salt is used as an active ingredient.

[0141] The anti-wetting agents include, but are not limited to, calcium carbonate, microcrystalline cellulose, fatty acid salts (Ca, Na, K and NH4), sodium carbonate, sodium bicarbonate, sodium bicarbonate, magnesium carbonate, magnesium hydroxide, magnesium oxide, amorphous silica, silicon dioxide, calcium silicate, magnesium silicate, talc, sodium aluminum silicate, sodium aluminum silicate, aluminum silicate, and the like.

[0142] The wetting agent includes, but is not limited to, sodium lactate, potassium lactate, sorbitol and sorbitol syrup, mannitol, glycerol, glycerol, xylitol, polydextrose, and the like.

[0143] The antioxidants include, but are not limited to, ascorbic acid, sodium ascorbate, calcium ascorbate, potassium ascorbate, isoascorbic acid, isoascorbic acid, sodium isoascorbate, sodium isoascorbate, lecithin, sodium lactate, citric acid, calcium citrate, tricalcium citrate, esters of citric acid and fatty acids with glycerol, citric acid with monoglycerides and diglycerides, and the like.

[0144] The thickener includes, but is not limited to, gelatin, alginic acid, sodium alginate, potassium alginate, ammonium alginate, calcium alginate, agar, carrageenan and its salts, jatan gum, carob, guar gum, tragacanth gum, gum arabic, gum arabic, xanthan gum, camphor gum, gellan gum, sorbitol and sorbitol syrup, konjac gum, pectin, amidated pectin, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, methylethyl cellulose, sodium carboxymethyl cellulose, polydextrose, and the like.

[0145] The stabilizer includes, but is not limited to, sodium caseinate, gelatin, calcium carbonate, calcium acetate, lecithin, monosodium citrate, disodium citrate, sodium citrate, trisodium citrate, potassium citrate, tripotassium citrate, calcium citrate, tricalcium citrate, alginic acid, sodium alginate, potassium alginate, ammonium alginate, calcium alginate, agar, carrageenan and its salts, giardia gum, locust bean, guar gum, tragacanth gum, gum arabic, gum arabic, xanthan gum, karaya gum, gellan gum, mannitol, konjac gum, pectin, amidated pectin, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, methylethyl cellulose, carboxymethyl cellulose Sodium acetate, fatty acid salts (Ca, Na, K and NH4), fatty acid monoglycerides and diglycerides, fatty acid monoglycerides and diglycerides, acetate esters and fatty acids and glycerol, acetate esters of monoglycerides and diglycerides, lactic acid esters of fatty acids and glycerol, lactic acid esters of monoglycerides and diglycerides, citric acid esters of fatty acids and glycerol, citric acid esters of glycerol monoglycerides and diglycerides, tartaric acid esters of fatty acids and glycerol, tartaric acid esters of glycerol monoglycerides and diglycerides, tartaric acid esters, acetic acid and esters of fatty acids and glycerol, sodium bicarbonate, sodium bicarbonate, potassium carbonate, calcium chloride, maltitol and maltitol syrup, polydextrose, etc.

[0146] The multivalent sequestrant includes, but is not limited to, citric acid, monosodium citrate, disodium citrate, sodium citrate, trisodium citrate, potassium citrate, tripotassium citrate, calcium citrate, tricalcium citrate, sorbitol and sorbitol syrup, acetate and acetate of monoglycerides and diglycerides of fatty acids, lactic acid esters of fatty acids and glycerol, lactic acid esters of monoglycerides and diglycerides, citrate esters of fatty acids and glycerol, citrate esters of monoglycerides and diglycerides, tartaric acid esters of glycerol and fatty acids, tartaric acid esters of monoglycerides and diglycerides, tartaric acid esters of acetic acid and fatty acids and glycerol, calcium sulfate, and the like.

[0147] The acidity regulator includes but is not limited to: calcium carbonate, acetic acid, calcium acetate, lactic acid, malic acid, fumaric acid, sodium lactate, potassium lactate, calcium lactate, citric acid, monosodium citrate, disodium citrate, sodium citrate, trisodium citrate, potassium citrate, tripotassium citrate, calcium citrate, tricalcium citrate, sodium carbonate, sodium bicarbonate, sodium carbonate, potassium carbonate, ammonium carbonate, ammonium bicarbonate, ammonium carbonate, magnesium carbonate, potassium sulfate, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, magnesium hydroxide, calcium oxide, gluconic acid, gluconolactone, calcium gluconate and the like.

[0148] The sweeteners include, but are not limited to, sucralose, aspartame, acesulfame potassium, saccharin sodium, cyclamate, thaumatin, stevioside, rebaudioside, neohesperidin dihydrochalcone, alitame or any mixture thereof.

[0149] In some embodiments, the food composition further comprises additional dietary supplements and / or food additives.

[0150] Specifically, the food composition comprises: vitamins, minerals, lycopene, lutein, carnitine, creatine, plant extracts, amino acids, peptides, proteins, and other nutrients such as plant oils of omega 3, omega 6, and omega 9 and their derivatives. Examples of minerals include zinc, calcium, magnesium, phosphorus, potassium, selenium, chromium, copper, manganese, cobalt, molybdenum, iodine, germanium, and mixtures thereof. Examples of vitamins include vitamin C, A, D, E, B vitamins, vitamin K, folic acid, and mixtures thereof.

[0151] Furthermore, the food composition also contains food raw materials.

[0152] The present invention provides a pharmaceutical composition, comprising the above-mentioned ammonium ferric citrate organic acid complex and / or its salt, and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient is selected from: one or more of a pharmaceutically acceptable carrier, a diluent, an excipient, a dispersant or a suspending agent, a surfactant, an isotonic agent, a thickener, an emulsifier, a preservative, a solid binder, a lubricant and a solvent.

[0153] The carrier refers to a pharmaceutically acceptable substance that can carry the active ingredient, improve its dispersibility, and has good chemical stability and adsorption, including but not limited to: different carriers can be applied to the preparation of pharmaceutically acceptable compositions and their well-known preparation methods.

[0154] The diluent refers to a substance that evenly distributes the additive raw material in the material and dilutes the high-concentration additive raw material into a low-concentration premix or premix, which can separate trace ingredients from each other and reduce the mutual reaction between active ingredients to increase the stability of the active ingredients without affecting the physicochemical properties of related substances.

[0155] The excipient is selected from one or more of a wetting agent that induces the inherent viscosity of the substance itself, a binder that makes the substance stick together, a disintegrant that breaks the whole sheet of the substance into many fine particles, a retention agent that reduces the friction between particles and an anti-sticking agent that prevents the material from sticking, including but not limited to: magnesium stearate, talc, vegetable oil, magnesium lauryl sulfate, starch, starch slurry, water, inorganic salts, dextrin or powdered sugar.

[0156] The solvent refers to a solvent required to dissolve or disperse a solid, including but not limited to: water, glycerol, and ethanol.

[0157] Specifically, the above-mentioned pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum protein, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, sodium dihydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose Cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol, phosphate buffer solution and other non-toxic suitable lubricants such as sodium laurate and magnesium stearate, colorants, release agents, coating materials, sweeteners, flavorings, fragrances, preservatives and antioxidants.

[0158] The pharmaceutical composition of the present invention refers to a compound group or collection comprising one or more compounds. The pharmaceutical composition can be used to prepare animal medicines and has a significant therapeutic effect on diarrhea in animals, especially livestock (such as weaned pigs) in the weaning stage.

[0159] In some embodiments, treatment refers to administering a therapeutic dose of the animal drug of the present invention to a sick animal to improve a disease or condition (i.e., slow down, organize or alleviate the development of the disease or at least one clinical symptom thereof); in other embodiments, treatment refers to administering a therapeutic dose of the animal drug of the present invention to a sick animal to alleviate or improve at least one physical parameter, including physical parameters that may not be perceived by the patient; in other embodiments, treatment refers to administering a therapeutic dose of the animal drug of the present invention to a sick animal to regulate the disease or condition physically (e.g., stabilize perceptible symptoms) or physiologically (e.g., stabilize physical parameters) or both; in other embodiments, treatment refers to administering a therapeutic dose of the animal drug of the present invention to a sick animal to prevent or delay the onset, occurrence or deterioration of a disease or condition.

[0160] The term "therapeutic dose" means the amount of a compound that, when administered to a diseased animal for treating a disease, is sufficient to be effective in treating the disease and may vary with the compound, the disease and the severity and condition, age, weight, sex of the animal to be treated.

[0161] In some embodiments, the pharmaceutical composition further comprises an additional drug for treating diarrhea in an animal.

[0162] The following is an explanation of the method of using the animal medicine of the present invention, the pharmaceutical composition of the present invention. The method of use for treating diarrhea in animals is to administer to sick animals a composition containing a therapeutic dose of ammonium ferric citrate organic acid complex and / or its salt, or a therapeutic dose of ammonium ferric citrate organic acid complex and / or its salt. The pharmaceutical composition of the present invention can be manufactured according to conventional methods disclosed in the art. The pharmaceutical composition is a unique target dosage form suitable for therapeutic purposes. The ammonium ferric citrate organic acid complex is mixed with a suitable drug diluent, excipient or carrier selected according to the form of administration and conventional pharmaceutical practice, for example, administered in an oral dosage form via a suitable carrier.

[0163] The pharmaceutical composition is used to treat diarrhea in animals. The oral dosage forms include but are not limited to oral enteric-coated dosage forms of tablets, pills or capsules. Farmers or veterinarians administer the oral dosage forms containing the pharmaceutical composition of the present invention to sick animals by gavage or by mixing with feed for administration.

[0164] The dosage regimen of the pharmaceutical composition of the present invention will vary with known factors, such as the pharmacokinetic characteristics of the specific agent and its mode and route of administration; the type, age and weight of the animal suffering from the disease; the nature and extent of the symptoms; the type of concurrent treatment; the frequency of therapeutic medication; the route of administration and the desired therapeutic effect. A veterinarian can make a decision and prescribe an effective amount of the drug to prevent, arrest, alleviate or slow the development of disease symptoms.

[0165] The pharmaceutical composition of the present invention is prepared into dosage unit form according to the formulation formula to reduce the dosage and dosage uniformity. Each unit dose of the formulation suitable for administration may contain 1 mg to 100 mg of ammonium ferric citrate organic acid complex and / or its salt. In these dosage forms, the weight of the active ingredient generally accounts for 0.5% to 95% of the total weight of the composition.

[0166] The above-mentioned "unit dose" refers to the physically dispersed unit of drug required for appropriate treatment of an organism. Specific implementation method:

[0167] In order to make the purpose, technical scheme and advantages of the present invention more clearly understood, the compounds, compositions and applications of the present invention are further described in detail below through examples. It should be understood that the specific examples described herein are only used to explain the present invention and are not intended to limit the present invention.

[0168] Example 1 Preparation of citric acid-fumaric acid complex.

[0169] The reagents involved in the preparation scheme include:

[0170] Ammonium ferric citrate, analytical grade (AR), was purchased from Shanghai Aladdin Biotechnology Co., Ltd. (Shanghai, China). The elemental analysis data showed that C 22.62%, H 4.18%, N 7.31%, and the XRD pattern was as follows: Figure 6 As shown, the DSC curve is Fig.11 shown.

[0171] Fumaric acid, analytical grade (AR), was purchased from Shanghai Aladdin Biotechnology Co., Ltd. (Shanghai, China). The XRD pattern is shown in Figure 7 As shown, the DSC curve is Fig.13 shown.

[0172] The FTIR spectrum of the mixture of ammonium ferric citrate and fumaric acid (referred to as the "mixture") with a molar ratio of 2:1 is as follows Fig. 9 As shown, the XRD spectrum is Fig.10 As shown, the DSC curve has an exothermic peak at 157.41℃. Fig.14 shown.

[0173] 1. Preparation of Ammonium Ferric Citrate-Fumaric Acid Complex A

[0174] Ammonium ferric citrate-fumaric acid complex A (hereinafter referred to as "complex A") is a product obtained during the preparation process in which the molar ratio of ammonium ferric citrate to fumaric acid is 1:1.

[0175] At room temperature, 150 mL of water and fumaric acid (43.8 g, 377 mmol) were added to the reaction bottle in sequence to form a reaction solution, and brown ammonium ferric citrate (100.0 g, 377 mmol) was dissolved in 200 mL of water to obtain a brown solution, which was added to the reaction bottle, heated, and the reaction system was heated to 50 ° C, stirred for 4.0 h to make the reaction solution clear, cooled to room temperature and continued to stir for 4 h. The reaction solution was filtered, the filtrate was concentrated and dried, and 1000 mL of ethanol was added and stirred for 3.0 h before filtering. The filter cake was washed with 500 mL of ethanol, dried at 55 ° C for 18 h, and sieved to obtain 104.5 g of complex A as a brown solid powder.

[0176] The structural characterization results of complex A are as follows:

[0177] (1) The elemental analysis data showed that C was 25.14%, H was 4.15%, N was 5.74%, and O was 48.84%. According to the law of conservation of elements, the content of iron (Fe) in the composite A was calculated to be about 16.13%.

[0178] (2) FTIR spectrum Figure 1 shown.

[0179] (3) XRD spectrum Figure 4 shown.

[0180] 2. Preparation of Ammonium Ferric Citrate-Fumaric Acid Complex B

[0181] Ammonium ferric citrate-fumaric acid complex B (hereinafter referred to as "complex B") is a product obtained during the preparation process in which the molar ratio of ammonium ferric citrate to fumaric acid is 2:1.

[0182] At room temperature, 50 mL of water and fumaric acid (21.9 g, 189 mmol) were added to the reaction bottle in sequence to form a reaction solution, and then brown ammonium ferric citrate (100.0 g, 377 mmol) was dissolved in 200 mL of water to obtain a brown solution, which was added to the reaction bottle, heated, and the reaction system was heated to 50 ° C, stirred for 1-1.5 h to make the reaction solution clear, cooled to room temperature and continued to stir for 5 h. The reaction solution was filtered, and the filtrate was concentrated and dried at 55-60 ° C to obtain a brown block hard solid. 500 mL of ethanol was added to the obtained solid, and the solid was scraped off with a scraper after standing, and the solid was magnetically stirred for 3.0 h and filtered. The filter cake was dried at 60 ° C overnight, sieved to obtain 115 g of brown solid powder, and the water content was 2.43% as measured by a moisture dryer.

[0183] The structural characterization results of complex B are as follows:

[0184] (1) The elemental analysis data showed that C was 25.82%, H was 4.09%, N was 6.19%, and Fe was 18.8%. According to the law of conservation of elements, the oxygen (O) content in the composite B was estimated to be about 42.69%.

[0185] (2) FTIR spectrum comparison results are as follows Figure 2 As shown, the samples corresponding to the spectra are, from top to bottom, ammonium ferric citrate fumaric acid complex B and ammonium ferric citrate and fumaric acid raw materials; Figure 2 It showed that there was no characteristic peak of fumaric acid in the ammonium ferric citrate fumaric acid complex B, and it was concluded that there was no free fumaric acid in the sample; Figure 2 and Fig. 9 The comparison shows that the material form of ammonium ferric citrate-fumaric acid complex B is different from the raw material mixture of ammonium ferric citrate and fumaric acid with the same molar ratio (i.e., the feed molar ratio is 1:1).

[0186] (3) XRD spectrum Figure 5 As shown, Figure 5 It showed that there was no characteristic peak of fumaric acid in complex B, and it was concluded that there was no free fumaric acid in the sample; Figure 5 and Fig.10 The comparison shows that the material form of complex B is different from the raw material mixture of ammonium ferric citrate and fumaric acid with the same molar ratio (i.e., the feed molar ratio is 1:1).

[0187] (4)DSC curve is as follows Fig.12 shown.

[0188] 3. Preparation of Ammonium Ferric Citrate-Fumaric Acid Complex C

[0189] Ammonium ferric citrate-fumaric acid complex C (hereinafter referred to as "complex C") is a product obtained during the preparation process when the molar ratio of ammonium ferric citrate to fumaric acid is 3:1.

[0190] At room temperature, 50 mL of water and fumaric acid (20.0 g, 172 mmol) were added to the reaction flask in sequence, and then brown ammonium ferric citrate (137 g, 517 mmol) was dissolved in 250 mL of water to obtain a brown solution, which was added to the reaction flask and heated to 50 ° C. The reaction solution was stirred for 1.5 h, cooled to room temperature, and continued to stir and react for 15 h. The reaction solution was filtered, the filtrate was concentrated to dryness, 1000 mL of ethanol was added, stirred and pulped for 4.0 h, and then filtered. The filter cake was washed with 500 mL, dried at 55 ° C for 18 h, and sieved to obtain 149.5 g of brown solid powder.

[0191] The structural characterization results of complex C are as follows:

[0192] (1) The elemental analysis data showed that the content of C was 23.8%, H was 4.29%, N was 6.14%, and O was 48.61%. According to the law of conservation of elements, the content of iron in the solid composite was estimated to be 17.16%.

[0193] (2) FTIR spectrum Figure 3 shown.

[0194] XRD spectrum Figure 8 shown.

[0195] Example 2 Stability Study of Ammonium Ferric Citrate-Fumaric Acid Complex

[0196] 1. Reagents:

[0197] Sulfuric acid, hydroxylamine hydrochloride, o-phenanthroline, acetic acid and sodium acetate were all analytically pure; ammonium ferric citrate-fumaric acid complex prepared in Example 1.

[0198] Acetic acid-sodium acetate buffer solution (pH 4.5): Accurately weigh 18 g of sodium acetate, add 9.8 mL of glacial acetic acid, dilute to 1000 mL with water, and shake well. 5% hydroxylamine hydrochloride solution: Accurately weigh 5 g of hydroxylamine hydrochloride, dissolve in water and dilute to 100 mL in a volumetric flask, and shake well.

[0199] 0.25% o-phenanthroline solution: Accurately weigh 0.25 g of o-phenanthroline, add appropriate amount of water, heat to dissolve, cool, dilute to 100 mL in a volumetric flask, and shake well.

[0200] 2. Instrument:

[0201] Drug stability test chamber, Shimadzu UV-1700 spectrophotometer, etc.

[0202] 3. Test methods and conditions

[0203] Preparation of ammonium ferric citrate standard solution :Accurately weigh 0.5 g (accurate to 0.0001 g) of ammonium ferric citrate standard, add 25 mL of 1% sulfuric acid solution, and dissolve by ultrasound at 65°C until the solution changes from dark brown to light yellow. Cool, dilute to 100 mL brown volumetric flask with 1% sulfuric acid, shake well, and prepare a standard stock solution with an iron mass concentration of 1000 μg / mL. Accurately measure 5 mL of the standard stock solution and put it into a 100 mL brown volumetric flask, dilute to volume with water, shake well, and prepare a standard working solution with an iron mass concentration of 50 μg / mL. Protect from light and store in a 4°C refrigerator for later use.

[0204] Drawing of standard curve of ammonium ferric citrate : Accurately measure 0, 0.2, 0.5, 1, 2, 3, 4 ammonium ferric citrate standard solution and place them in a 50mL brown volumetric flask, add 2ml of hydroxylamine hydrochloride solution, 2ml of o-phenanthroline solution and 10ml of acetic acid-sodium acetate buffer solution, dilute with water to the scale, shake well, and obtain Fe(II) standard solutions with concentrations of 0.00μg / mL, 0.20μg / mL, 0.50μg / mL, 1.00μg / mL, 2.00μg / mL, 3.00μg / mL, and 4.00μg / mL, respectively. Place them in a constant temperature box at 37℃ for color development for 80min, take 0.00μg / mL as blank, measure the absorbance of the standard solution at a wavelength of 510nm, and draw a standard curve with the concentration of Fe(II) solution as the horizontal axis and the absorbance value as the vertical axis.

[0205] Preparation of test solution : Accurately weigh 50-100 mg (accurate to 0.1 mg) of the sample into a stoppered Erlenmeyer flask, accurately add 50 mL of 1% sulfuric acid solution, stopper and seal, ultrasonically dissolve at 65°C until the solution changes from dark brown to light yellow, cool, and test immediately.

[0206] Preparation of blank solution : Accurately measure 5.00 mL of the test solution and place it in a brown volumetric flask. Add 10 mL of acetic acid-sodium acetate buffer solution (3.7), dilute to the scale with water and shake well; place in a constant temperature box at 37°C for 80 min.

[0207] Determination of test solution : Accurately measure 5.00mL of the test solution and place it in a brown volumetric flask. Add 2mL of o-phenanthroline solution and 10mL of acetic acid-sodium acetate buffer solution, dilute to the scale with water and shake well. Place it in a constant temperature box at 37°C for 80 minutes to develop color. Use the blank test solution as blank and measure the absorbance at a wavelength of 510nm. Calculate the concentration of Fe(II) in the test solution according to the standard curve.

[0208] 25℃, 75±5%RH high humidity stability test and its results Samples of ammonium ferric citrate, complex A, complex B and complex C were placed in a culture dish, spread into a thin layer of ≤5 mm, and placed in a high humidity environment of 25°C and 75±5%RH. Samples were taken for testing on the 5th and 10th days, and each sample was sampled twice in parallel.

[0209] Light stability test and its results : Samples of ammonium ferric citrate, complex A, complex B and complex C were placed in a culture dish, spread into a thin layer of ≤5 mm, placed in a 4500Lx±500Lx light environment, and sampled for detection on the 0th day, 5th day and 10th day, with each sample sampled twice in parallel. The measurement result is the arithmetic mean of the two parallel measurement values, retained to two decimal places, and ΔFe(II) (%) is used to represent the percentage change of Fe(II) in the sample. The Fe(II) content (%) expressed as mass percentage is calculated according to formula (1).

[0210]

[0211] In the formula: C is the concentration of Fe(II) in the sample to be tested calculated according to the standard curve, in micrograms per milliliter (μg / mL); V is the total volume of the sample, in milliliters (mL); D is the dilution factor of the sample; m is the mass of the sample, in milligrams (mg).

[0212] 4. Results and Conclusions

[0213] (1) The physical stability of ammonium ferric citrate and its complex B was mainly investigated under high humidity conditions of 75±5%RH, and the changes in appearance. The results are shown in Table 1. The results show that the moisture absorption of the ammonium ferric citrate-fumaric acid complex was improved by 41.3% compared with ammonium ferric citrate on the 10th day of the test [this value = [(moisture absorption weight gain of ammonium ferric citrate) - (moisture absorption weight gain of ammonium ferric citrate fumaric acid complex B)] / (moisture absorption weight gain of ammonium ferric citrate) * 100%], and the appearance of the ammonium ferric citrate fumaric acid complex sample remained basically unchanged during the test, while the ammonium ferric citrate changed from rust-colored powder to black colloidal liquid due to moisture absorption.

[0214] Table 1 High humidity stability study results of ammonium ferric citrate and ammonium ferric citrate fumarate complex B

[0215]

[0216] (2) The chemical stability of ammonium ferric citrate and ammonium ferric citrate-fumaric acid complex B was mainly investigated under light conditions to investigate the changes in the content of Fe(II) in ammonium ferric citrate and its complex, and the results are shown in Table 2. The results showed that under light conditions, compared with ammonium ferric citrate, the content of ΔFe(II) in ammonium ferric citrate-fumaric acid complex B decreased by about 16.25% on the 10th day (this value = [ΔFe(II) of ammonium ferric citrate - ΔFe(II) of ammonium ferric citrate-fumaric acid complex] / ΔFe(II) of ammonium ferric citrate * 100%), and the stability increased significantly.

[0217] Table 2 Results of the light stability study of ammonium ferric citrate and ammonium ferric citrate fumarate complex B

[0218]

[0219] Example 3 Effect of Ammonium Ferric Citrate Fumarate Complex on Growth Performance and Diarrhea in Piglets

[0220] 140 45-day-old Duroc-Changda lean piglets of similar weight were randomly divided into 7 treatment groups, with 2 replicates in each group, half male and half female, and 10 pigs in each replicate. The specific groups are shown in Table 3. The pig sty and utensils were disinfected before the experiment. The pigs were kept in separate pens under the same feeding and management conditions in the same pig sty during the trial period. During the trial, the experimental pigs had free access to food and water. Among them, Group A was the blank control group, which was only given nursery feed; the experimental BD groups were given nursery feed containing different amounts of ammonium ferric citrate, and the experimental EG groups were given nursery feed containing different amounts of ammonium ferric citrate fumaric acid complex B (referred to as "complex B") prepared in Example 1. No other antioxidant ingredients and growth promoters were added to the experimental groups during the entire feeding process. The experimental period was 28 days, and the growth performance of the experimental pigs was statistically analyzed. The average daily feed intake (ADFI, g / d*head), average daily weight gain (ADG, g / d*head), feed-to-meat ratio (FCR) and diarrhea rate of the experimental pigs are expressed as “average values”, as shown in Table 3.

[0221] Feed to meat ratio (FCR) = average daily feed intake / average daily weight gain;

[0222] Weight gain rate = (ADG of the experimental group - ADG of the control group) / ADG of the control group * 100%;

[0223] Feed intake increase rate = (ADFI of the experimental group - ADFI of the control group) / ADFI of the control group * 100%;

[0224] Feed-to-meat ratio reduction rate = (control group FCR - control group experimental group FCR) / control group FCR * 100%;

[0225] Diarrhea improvement rate = (diarrhea rate in the experimental group - diarrhea rate in the control group) / diarrhea rate in the control group * 100%.

[0226] Table 3 Effect of ammonium ferric citrate fumarate complex on growth performance of piglets

[0227]

[0228]

[0229] From the above test results, it can be seen that compared with the blank control group, the experimental group given nursery feed containing ammonium ferric citrate or its fumaric acid complex had a significant improvement in the feed intake, average daily weight gain, feed-to-meat ratio and diarrhea rate of the experimental pigs.

[0230] When ammonium ferric citrate was added to the nursery feed, the feed intake of the experimental pigs increased by 13.62%-15.29%, the body weight increased by 22.68%-30.33%, the feed-to-meat ratio decreased by 7.69%-11.79%, and the diarrhea rate decreased by 23.37%-69.04%.

[0231] When ammonium ferric citrate fumarate complex was added to the nursery feed, the feed intake of the experimental pigs increased by 14.31%-16.41%, the body weight increased by 23.50%-32.79%, the feed-to-meat ratio decreased by 6.67%-13.85%, and the diarrhea rate decreased by 17.40%-69.16%.

[0232] It can be seen that the effect of ammonium ferric citrate organic acid complex on the growth performance and diarrhea rate of the test pigs is comparable to or even better than that of ammonium ferric citrate, especially when used at a dosage of 500-1000ppm, and can be used as an equivalent substitute for ammonium ferric citrate in pig feed. In addition, the results compared with the blank control also show that the ammonium ferric citrate fumaric acid complex increases the growth rate of the test pigs by increasing the feed intake and feed conversion rate, and increases the feed return rate, and can be used as a new feed additive in pig farming.

[0233] Example 4 Effect of Ammonium Ferric Citrate Fumarate Complex on Growth Performance of Broilers

[0234] The experiment adopted a single-factor random design, and 240 three-yellow-feathered broilers of 1 day old, similar weight and average weight of 50g were selected and randomly divided into 4 treatment groups, with 3 replicates in each group, 20 three-yellow-feathered broilers in each replicate, half male and half female, and the groups are shown in Table 4. The chicken house and utensils were disinfected before the experiment. Cages were raised under the same feeding and management conditions in the same chicken house during the experimental period. The basic diet was mainly corn-soybean meal, and no other antioxidant ingredients and growth promoters were added during the entire feeding process. Among them, experiment A was a blank control group that was only given a basic diet, and experiments B to D groups added different doses of ammonium ferric citrate fumarate complex B to the basic diet, as shown in Table 4. The experimental period was 20 days, and the experimental chickens had free access to water and food, and were fed twice a day. Each replicate was taken as a unit, and the chickens were weighed at 21 days of age (feed was stopped for 12 hours, water was not stopped), and the feed consumption of the experimental chickens was counted. The average daily feed intake (ADFI, g / d*bird), average daily weight gain (ADG, g / d*bird) and feed-to-meat ratio (FCR) of each group of experimental chickens were calculated. The calculation formula is as follows:

[0235] Feed to meat ratio (FCR) = average daily feed intake / average daily weight gain;

[0236] Weight gain rate = (ADG of the experimental group - ADG of the control group) / ADG of the control group * 100%;

[0237] Feed intake increase rate = (ADFI of the experimental group - ADFI of the control group) / ADFI of the control group * 100%;

[0238] Feed-to-meat ratio reduction rate = (control group FCR - control group experimental group FCR) / control group FCR * 100%.

[0239] The test results are shown in Table 4. From the results, it can be seen that compared with the control group:

[0240] Compared with the control group, the feed intake and average daily weight gain of the experimental group of chickens in the basic diet supplemented with ammonium ferric citrate fumarate complex B increased by 6.96%-22.47% and 11.72%-32.03%, respectively, and showed an upward trend with the increase of dosage; the feed-to-meat ratio decreased by about 4.45%-7.29%, and the feed conversion rate improved.

[0241] It can be seen that the application of ammonium ferric citrate fumarate complex B in broiler feed can effectively promote the growth of experimental chickens and improve feed conversion. It can be used in broiler feed as an effective feed additive to promote the growth of broilers and improve breeding efficiency and benefits.

[0242] Table 4 Application effect of ammonium ferric citrate fumarate complex B in broiler feed

[0243]

[0244] Example 5 Study on the application of ammonium ferric citrate fumarate complex B in meat duck feed

[0245] A single-factor experimental design was adopted. 480 Cherry Valley ducks of 1 day old, basically the same body weight and in good health were selected and randomly divided into 4 treatments, with 6 replicates in each treatment and 20 ducks in each replicate. The control group was fed with blank feed and a corn-soybean meal-based basal diet. The other 4 treatment groups were sample-added groups, with different doses of ammonium ferric citrate organic acid complex B added to the basal diet. The experiment lasted for 42 days. The specific animal groupings are shown in Table 5. During the experiment, the ducks were allowed to eat and drink freely, and were immunized according to the routine immunization procedures. The feeding conditions, feed consumption, and mortality of each group of experimental ducks were observed and recorded every day. The ducks were weighed on an empty stomach at the beginning and end of the experiment. After the experiment, the average daily weight gain, average daily feed intake and feed-to-meat ratio of each treatment group were statistically analyzed in units of replicates. The results are shown in Table 5.

[0246] From the results presented in Table 5, it can be seen that compared with the control group, the addition of ammonium ferric citrate fumarate complex B in the feed of Cherry Valley ducks aged 1-42 days can significantly improve the production performance of ducks. At the experimental dosage, the feed intake, weight gain rate and feed-to-meat ratio decreased by 2.40%-6.24%, 7.64%-15.72% and 4.78-8.26%, respectively. It can be seen that ammonium ferric citrate fumarate complex B can increase the feed intake of experimental ducks and reduce the feed-to-meat ratio, that is, improve the feed conversion rate, thereby promoting the growth of experimental ducks by increasing their feeding and improving feed conversion, thereby improving feed remuneration, and can be used as a feed additive to promote the growth of ducks.

[0247] Table 5 Application effect of ammonium ferric citrate fumarate complex B in meat duck feed

[0248]

[0249] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. An ammonium ferric citrate organic acid complex or a salt thereof, characterized in that: The complex comprises ammonium ferric citrate and an organic acid, wherein the organic acid is selected from fumaric acid, maleic acid, succinic acid, malonic acid, oxalic acid, benzoic acid, sorbic acid or an acidic amino acid, and the acidic amino acid is selected from glutamic acid or aspartic acid; preferably, the organic acid is fumaric acid or maleic acid; more preferably, the salt of the ammonium ferric citrate organic acid complex is ammonium ferric citrate organic acid complex sodium salt.

2. The ammonium ferric citrate organic acid complex or its salt according to claim 1, characterized in that: It also contains at least one solvent that can solvate ammonium ferric citrate and an organic acid; preferably, the solvent is selected from water, methanol, ethanol, methanol aqueous solution or ethanol aqueous solution; more preferably, the ammonium ferric citrate organic acid complex or its salt is used as a medicine, feed, or food; further preferably, the ammonium ferric citrate organic acid complex or its salt is used as a medicine for preventing and treating animal diarrhea.

3. A method for preparing the ammonium ferric citrate organic acid complex or its salt according to claim 1 or 2, comprising the following steps: (1) dissolving an organic acid or a salt thereof to obtain an organic acid or a salt thereof solution; (2) dissolving ammonium ferric citrate to obtain an ammonium ferric citrate solution; (3) adding the ammonium ferric citrate solution to the organic acid or its salt solution to obtain a reaction solution, and stirring the solution under heating for 1-4 hours; (4) stirring the reaction solution after step (3) at room temperature for 4-15 hours; (5) filtering the reaction solution after step (4), concentrating and drying the filtrate to obtain an ammonium ferric citrate organic acid complex or its salt.

4. The preparation method according to claim 3, characterized in that: In the preparation method, the molar ratio of ammonium ferric citrate to the organic acid is 1:1-3:1; preferably, the molar ratio of ammonium ferric citrate to the organic acid is 2:1; preferably, the heating temperature is 25-60°C; more preferably, the organic acid is fumaric acid or maleic acid.

5. A composition, characterized in that Comprising the ammonium ferric citrate organic acid complex or its salt as described in claim 1 or 2; preferably, the composition is used as a medicine, feed, or food.

6. A feeding composition, characterized in that: The composition comprises the ammonium ferric citrate organic acid complex or its salt as described in claim 1 or 2, and one or more of a carrier, excipient, diluent, and solvent acceptable to feed; preferably, the composition further comprises additional feed additives and / or feed raw materials, and more preferably, the feed additives are selected from nutritional feed additives or non-nutritional feed additives.

7. An edible composition, characterized in that The composition comprises the ammonium ferric citrate organic acid complex or its salt as described in claim 1 or 2, and nutritionally acceptable auxiliary materials; preferably, the composition further comprises additional dietary supplements and / or food additives and / or food raw materials.

8. A pharmaceutical composition, characterized in that The composition comprises the ammonium ferric citrate organic acid complex or its salt as described in claim 1 or 2, and pharmaceutically acceptable excipients. Preferably, the composition further comprises an additional drug for treating animal diarrhea.

9. Use of the ammonium ferric citrate organic acid complex or its salt according to claim 1 or 2 or the composition according to any one of claims 5 to 8 as or in the preparation of an animal feed additive, preferably, the animal feed additive is selected from animal iron supplements and / or animal growth promoters.

10. Use of the ammonium ferric citrate organic acid complex or its salt according to claim 1 or 2 or the composition according to any one of claims 5 to 8 as or in the preparation of a food additive, preferably, the food additive is a food iron fortifier.

11. Use of the ammonium ferric citrate organic acid complex or its salt according to claim 1 or 2 or the composition according to any one of claims 5 to 8 in the preparation of a medicament for preventing and treating diarrhea in animals.

12. A method for raising animals, comprising administering the ammonium ferric citrate organic acid complex and / or its salt according to claim 1 or 2, or the composition according to any one of claims 5 to 8 to the animals.

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