Preparation method of iron supplementing agent ferrous succinate with low iron content and iron content

Abstract

The invention relates to a preparation method of iron supplement medicine ferrous succinate with low high iron content, succinic acid and ferrous sulfate heptahydrate are used as raw materials to generate ferrous succinate, the high iron content of the raw material ferrous sulfate is controlled, the oxygen content of water for reaction is controlled in the reaction process, and meanwhile, the process conditions are controlled, so that the iron supplement medicine ferrous succinate with low high iron content is obtained. And finally obtaining the ferrous succinate with the high iron content of less than 0.2%. The synthesis method is simple, conditions are easy to control, the production safety is high, the product yield is high, and ferrous succinate with very low high iron content can be obtained.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and particularly relates to a method for preparing an iron supplement ferrous succinate with low iron content. Technical Background

[0002] Iron is a vital element for the human body, participating in the synthesis of hemoglobin and playing a crucial role in oxygen transport and metabolic processes. Iron is a major component of hemoglobin and myoglobin, with hemoglobin being the primary oxygen carrier in red blood cells. Iron-deficiency anemia and other iron-deficiency disorders caused by iron deficiency are common worldwide, with the highest incidence among infants and young children. Iron-deficiency anemia is a major issue affecting adolescent development and overall health. Oral iron supplements are used to prevent or treat iron deficiency caused by various factors, such as increased iron requirements during childhood and infancy, insufficient dietary iron supply, iron malabsorption, pregnant women in their second and third trimesters, and patients with chronic blood loss. Iron deficiency can lead to not only decreased hemoglobin synthesis and oxygen-carrying capacity, but also symptoms related to tissue iron deficiency and reduced iron-containing enzyme activity, such as growth retardation, abnormal movement, lack of strength, changes in mucous membranes, and skin and nail lesions. These symptoms can gradually resolve with iron supplementation.

[0003] Organic iron and ferrous iron are not easily absorbed by the human body. Oral iron supplements are generally inorganic or small-molecule organic ferrous salts (single salt or complex), such as ferrous sulfate, ferrous fumarate, ferrous lactate, ferrous gluconate, and ferrous succinate. Ferrous succinate, listed in the 1973 edition of the British Pharmacopoeia, is relatively mild in digestive tract irritation and has relatively high bioavailability among these iron supplements. Ferrous succinate tablets were approved for production in China on May 20, 1993. National drug standards stipulate that the ferrous iron content in ferrous succinate must not exceed 2.0%, and in preparations, 3.0%. The ferrous iron content in ferrous succinate increases significantly during its distribution after it is formulated into preparations. Therefore, reducing the ferrous iron content in ferrous succinate is important for improving the absorption and utilization of the iron in ferrous succinate and extending the shelf life of ferrous succinate preparations. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to reduce the ferrous iron content in ferrous succinate, thereby reducing the ferrous iron content in ferrous succinate preparations. The present invention provides a method for preparing ferrous succinate with a low ferrous iron content that is suitable for industrial implementation. The ferrous succinate raw material has a very low ferrous iron content, its total iron content meets the pharmacopoeial standards, and the process is not complicated and has good reproducibility.

[0005] The present invention relates to an iron supplement ferrous succinate, the structural formula of which is as follows:

[0006]

[0007] The present invention provides a method for preparing ferrous succinate with low iron content, the steps of which are as follows:

[0008] a) adding ferrous sulfate heptahydrate to low-oxygen water, heating (preferably to 50-60° C.) under N2 protection, stirring and dissolving to obtain a ferrous sulfate solution;

[0009] b) adding sodium hydroxide and a certain amount of succinic acid to low-oxygen water, stirring and dissolving under nitrogen protection to obtain an alkaline solution of succinic acid;

[0010] c) heating the alkaline solution of succinic acid to a certain temperature under N2 protection, then adding the ferrous sulfate solution dropwise, heating the solution to a certain temperature after the addition, and stirring the reaction for a certain time;

[0011] d) cooling to a certain temperature, filtering, rinsing with low-oxygen water, then rinsing with an organic solvent (containing succinic acid), and vacuum drying to obtain the target compound ferrous succinate.

[0012] In the preparation method of the present invention, the ferrous sulfate heptahydrate used should have an iron content of less than 0.1% (W / V), and the oxygen content of the low-oxygen water used should be less than 0.5 mg / L.

[0013] In the preparation method of the present invention, the amount of succinic acid in reaction step b) can vary within a certain range, and the molar ratio of succinic acid to the amount of ferrous sulfate raw material is 0.8:1 to 1:1, preferably 0.9:1.

[0014] In the preparation method of the present invention, the temperature during the dropwise addition in reaction step c) can be room temperature to 80°C, preferably 50 to 60°C.

[0015] In the preparation method of the present invention, the reaction temperature is 60°C to 100°C, preferably 90°C to 100°C.

[0016] In the preparation method of the present invention, the reaction time of step c) can be 1 to 10 hours, preferably 2 to 3 hours, and more preferably, the reaction time is 3 hours.

[0017] In the preparation method of the present invention, the filtration temperature in reaction step d) can be 10°C to 40°C, preferably 20°C to 30°C.

[0018] In the preparation method of the present invention, the organic solvent used for elution in reaction step d) is a water-soluble organic solvent, which can be one or a mixture of methanol, ethanol, propanol, isopropanol, acetone, dimethyl sulfoxide, N,N-dimethylformamide, and N,N-dimethylacetamide, preferably methanol, ethanol, acetone, and more preferably ethanol.

[0019] In the preparation method of the present invention, the organic solvent used for elution in reaction step d) contains a certain amount of succinic acid, the content of which may be 0.1% to 0.5% (w / v), preferably 0.1% (w / v).

[0020] In a preferred example of the present invention, the molar ratio of succinic acid to ferrous sulfate raw material is 0.9:1; step a) is heated to 50°C; the temperature during the dropwise addition in reaction step c) is 50-60°C; the reaction temperature is 90-100°C; the reaction time in reaction step c) is 2h-3h, and the reaction time is 3h; the filtration temperature in reaction step d) is 20°C-30°C; the succinic acid content in the organic solvent used for elution in reaction step d) is 0.1% (w / v); the organic solvent used for elution in reaction step d) is methanol or ethanol. DETAILED DESCRIPTION

[0021] The present invention will be further described below in conjunction with specific embodiments:

[0022] Example 1:

[0023] (1) Add 300 g of ferrous sulfate heptahydrate and 300 ml of deoxygenated water into a 500 ml three-necked flask, replace the atmosphere with nitrogen, heat to 50-60°C, and stir to dissolve to obtain a ferrous sulfate solution.

[0024] (2) 89.18 g of sodium hydroxide and 141.34 g of succinic acid were added to 208.1 ml of low-oxygen water, and the mixture was heated to 50-60° C. after nitrogen substitution and stirred to dissolve, thereby obtaining an alkaline solution of succinic acid.

[0025] (3) Under N2 protection, the temperature was controlled at 50-60℃ and the ferrous sulfate solution was added dropwise. After the addition was completed, the temperature was raised to 90-100℃ and stirred for a certain time. The reaction was kept warm for 3 hours.

[0026] (4) Cool to 20-30°C, filter, rinse with 600 ml of low-oxygen water, then rinse with ethanol (containing 0.1% succinic acid), and dry in a vacuum at 75°C.

[0027] A total of 154.01 g of ferrous succinate was obtained with a yield of 83%. According to the National Bureau of Drug Standard YBH000682017, the total iron content was 35.2% and the high iron content was 0.09%.

[0028] Example 2:

[0029] (1) Add 2.4 kg of ferrous sulfate heptahydrate and 2.4 L of deoxygenated water into a 10 L kettle, replace the atmosphere with nitrogen, heat to 50-60 °C, and stir to dissolve to obtain a ferrous sulfate solution.

[0030] (2) 713.44 g of sodium hydroxide and 1130.72 g of succinic acid were added to 1664.8 ml of low-oxygen water, and after nitrogen replacement, the temperature was raised to 50-60° C. and stirred to dissolve, thereby obtaining an alkaline solution of succinic acid.

[0031] (3) Under N2 protection, the temperature was controlled at 60-70°C and the ferrous sulfate solution was added dropwise. After the addition, the temperature was raised to 90-100°C and the reaction was kept warm for 3 hours.

[0032] (4) Cool to 20-30°C, filter, rinse with 600 ml of low-oxygen water, then rinse with methanol (containing 0.1% succinic acid), and dry in a vacuum at 75°C.

[0033] The obtained product was dried to obtain 1160.42 g of ferrous succinate with a yield of 78%. According to the National Bureau of Drug Standard YBH000682017, the total iron content was 34.5% and the ferrous content was 0.14%.

[0034] Comparative Example:

[0035] (1) Add 152.4 g of sodium hydroxide to 550 ml of purified water, stir and dissolve, slowly add 225.0 g of succinic acid, stir and dissolve to obtain an alkaline solution of succinic acid.

[0036] (2) Add 529.5 g of ferrous sulfate heptahydrate and 350 ml of purified water into a three-necked flask, replace the atmosphere with nitrogen, heat to 50-60° C., and stir to dissolve to obtain a ferrous sulfate solution.

[0037] (3) Under N2 protection, the temperature was controlled at 90-100℃ and the ferrous sulfate solution was added dropwise. After the addition was completed, the temperature was raised to 90-100℃ and stirred for a certain time. The reaction was kept warm for 3 hours.

[0038] (4) Filter while hot, rinse with 600 ml of 0.1% (w / v) succinic acid solution, then rinse with ethanol, and dry in a vacuum at 75°C.

[0039] A total of 230.21 g of ferrous succinate was obtained. According to the National Bureau of Drug Standard YBH000682017, the total iron content was 35.7% and the high iron content was 0.69%.

Claims

1. A method for preparing ferrous succinate with low iron content, wherein the ferrous succinate has the following structural formula: It is characterized by The steps include: a) adding ferrous sulfate heptahydrate to low-oxygen water, heating and stirring under N2 protection to dissolve, to obtain a ferrous sulfate solution; b) adding sodium hydroxide and succinic acid to low-oxygen water, stirring and dissolving under N2 protection to obtain an alkaline solution of succinic acid; c) heating the alkaline solution of succinic acid under N2 protection, then adding the ferrous sulfate solution dropwise, heating the solution after addition, and stirring to react; d) cooling the reaction solution of step c), filtering, rinsing with water containing low oxygen content, then rinsing with an organic solvent containing succinic acid, and vacuum drying to obtain ferrous succinate with low iron content.

2. The preparation method according to claim 1, wherein The ferrous sulfate heptahydrate has an iron content of less than 0.1%.

3. The preparation method according to claim 1, wherein The oxygen content of the low-oxygen water is less than 0.5 mg / L.

4. The preparation method according to claim 1, wherein In the reaction step b), the molar ratio of succinic acid to ferrous sulfate heptahydrate is 0.8:1 to 1.1:

1.

5. The preparation method according to claim 1, wherein Reaction step c) Under N2 protection, the alkaline solution of succinic acid is heated, and then the ferrous sulfate solution is added dropwise at a temperature of 60°C to 80°C.

6. The preparation method according to claim 1, wherein Reaction step c) Under N2 protection, the alkaline solution of succinic acid is heated and then the ferrous sulfate solution is added dropwise. The reaction temperature is 90-100°C after the addition is completed.

7. The preparation method according to claim 1, wherein The reaction time of the reaction step c) is 1 to 10 hours.

8. The preparation method as claimed in claim 1, characterized in that The filtration temperature in the reaction step d) is 10°C to 40°C.

9. The preparation method according to claim 1, wherein The organic solvent in reaction step d) is selected from one or a mixture of methanol, ethanol, propanol, isopropanol, acetone, dimethyl sulfoxide, N,N-dimethylformamide, and N,N-dimethylacetamide.

10. The preparation method according to claim 1, wherein The content of succinic acid in the organic solvent in reaction step d) is 0.1% to 0.5% (w / v).

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