A method for preparing carboxymethyl maltose iron

Abstract

This invention belongs to the field of pharmaceutical synthesis and discloses a method for preparing carboxylated maltose iron, comprising: adding sodium carbonate solution to a mixture of carboxylated maltodextrin solution and ferric chloride solution in two separate additions, controlling the amount of sodium carbonate solution added in the first addition to be 20-40% of the total amount of sodium carbonate solution, and the time interval between the two additions of sodium carbonate solution to be 10-40 minutes, to obtain carboxylated maltose iron with the target molecular weight and molecular weight distribution coefficient. In actual production, this invention not only significantly reduces the reaction temperature but also significantly reduces the complexation reaction time, achieving the effect of shortening the reaction cycle and saving energy. While ensuring the acquisition of carboxylated maltose iron with the target molecular weight and molecular weight distribution, it conforms to the trend of energy conservation and environmental protection, and has significant practical value.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis and relates to a method for preparing carboxymaltose iron, specifically a method for controlling the molecular weight of carboxymaltose iron in the synthesis reaction of carboxymaltose iron, which is applicable to the control of the molecular weight of the final product carboxymaltose iron in the synthesis process of carboxymaltose iron. Background Technology

[0002] Iron deficiency anemia is a common nutritional disorder caused by insufficient iron stores in the body to meet the needs of normal red blood cell production. Carboxymaltose iron is a novel drug for the treatment or prevention of iron deficiency anemia. Developed by Vifor Pharmaceuticals, carboxymaltose iron injection was first launched in Germany in November 2007, followed by launches in the UK, Switzerland, and several other countries. Its indication is iron deficiency anemia that is unresponsive to or cannot be treated orally.

[0003] The synthetic route for carboxy-modified maltose iron is as follows:

[0004]

[0005] The pH of the maltodextrin solution was controlled at 9.0–11.0 using sodium hydroxide solution. Sodium bromide was used as a catalyst, and the maltodextrin solution was moderately oxidized to carboxylated maltodextrin solution with 10% sodium hypochlorite solution. The carboxylated maltodextrin solution and ferric chloride solution were complexed under sodium carbonate conditions and then solidified with alkali, acid, and heat to produce carboxylated ferric malt solution. The carboxylated ferric malt solution was crystallized with ethanol, purified, and dried to obtain carboxylated maltose iron.

[0006] The molecular weight of carboxymaltose iron is mainly expressed as weight-average molecular weight (Mw). Carboxymaltose iron with different molecular weight distributions exhibits unique characteristics in terms of solubility, bioavailability, and stability. The molecular weight of carboxymaltose iron determines its pharmacological and biological properties. The molecular weight plays a major role in its distribution and metabolism in vivo. Therefore, in actual production, carboxymaltose iron with different weight-average molecular weights (110,000–230,000) can be produced within a certain range according to actual needs.

[0007] Currently, the molecular weight properties of carboxymaltose iron for iron supplementation are typically characterized as follows: weight-average molecular weight (Mw): 110,000–230,000, number-average molecular weight (Mn): ≥60,000, and molecular weight distribution coefficient (Mw / Mn) ≤1.9. The original drug's multiple batches have weight-average molecular weights controlled between 165,000 and 175,000.

[0008] Related patents or patent applications CN106977621A, CN108129582A, and CN1705682A (original research patent) all involve the synthesis of carboxylated maltose iron, but none of them provide a detailed description of the molecular weight control of carboxylated maltose iron. CN1705682A and related literature, however, describe obtaining the desired molecular weight and distribution of carboxylated maltose iron by controlling the dextran equivalent of maltodextrin.

[0009] Current methods for controlling the molecular weight of carboxymaltose iron generally involve adjusting the molecular weight by controlling the dropping rate of the sodium carbonate solution during the complexation process. However, this method has certain limitations in actual production:

[0010] 1. The process has high requirements: it is necessary to ensure uniform dripping, which is difficult to meet with ordinary high-level tanks. Generally, a constant flow pump is required, which increases the equipment, complicates the on-site pipeline layout, and also increases costs.

[0011] 2. Strict requirements for dripping speed: The dripping speed of sodium carbonate solution will vary slightly depending on the amount of material added, and needs to be adjusted according to the actual production site. The process is relatively complex and lacks stability and reliability.

[0012] 3. Longer dripping time: In actual production, the dripping time of sodium carbonate solution exceeds 3 hours in order to obtain a molecular weight and distribution similar to the original drug.

[0013] 4. The temperature of the complexation stage when adding sodium carbonate solution is generally above 60℃. The reaction temperature is high and the energy consumption is relatively large. Summary of the Invention

[0014] The purpose of this invention is to provide a simple and effective method for controlling the molecular weight of carboxymaltose iron, obtaining carboxymaltose iron with different molecular weights in the synthesis reaction of carboxymaltose iron, and by adjusting the process parameters, especially under the preferred process parameters, carboxymaltose iron within the original molecular weight range can be obtained.

[0015] Carboxymaltose iron is generally produced by oxidizing maltodextrin under alkaline conditions with hypochlorous acid to obtain carboxymaltodextrin, which then reacts with ferric chloride to form a large molecular compound with an iron ion core and a carboxymaltodextrin shell, possessing a stable spatial structure. The final molecular weight distribution of carboxymaltose iron is closely related to the reaction process and related parameters.

[0016] The inventors made a creative discovery: In the complexation reaction system of ferric chloride solution and carboxymaltodextrin solution, by fixing the ratio of sodium carbonate to ferric chloride, the concentration of sodium carbonate solution, and the concentration of ferric chloride solution, and by adding sodium carbonate solution in two separate additions, and by controlling the amount of sodium carbonate solution added each time and the time interval between the two additions, carboxymaltodextrin iron with different target molecular weights and molecular weight distribution coefficients can be obtained.

[0017] The molecular weight of carboxymaltose iron is independent of the amount of material in the reaction system. By adjusting the relevant process parameters, carboxymaltose iron with a specific molecular weight and molecular weight distribution coefficient can be obtained, achieving the same molecular weight and molecular weight distribution as the original drug.

[0018] The objective of this invention is achieved through the following technical solution:

[0019] A method for preparing carboxymaltose iron includes: adding sodium carbonate solution to a mixture of carboxymaltodextrin solution and ferric chloride solution in two separate additions, controlling the amount of sodium carbonate solution added in the first addition to be 20-40% of the total amount of sodium carbonate solution, and the time interval between the two additions of sodium carbonate solution to be 10-40 minutes, to obtain carboxymaltose iron with a target molecular weight and molecular weight distribution coefficient.

[0020] The weight ratio of carboxylated maltodextrin (based on raw maltodextrin) to ferric chloride (based on ferric chloride hexahydrate) is 7:13.

[0021] According to the requirements of this invention, the ratio of ferric chloride to sodium carbonate is fixed, and the weight ratio of ferric chloride to sodium carbonate is 2:1 to 3:1, calculated as ferric chloride hexahydrate.

[0022] The concentration of ferric chloride in the ferric chloride solution is 25-30% (w / w).

[0023] The concentration of sodium carbonate in the sodium carbonate solution is 15-25% (w / w).

[0024] As a preferred technical solution of the present invention, the carboxymethyl maltodextrin solution and the ferric chloride solution are first mixed evenly, and the temperature is controlled at 30-40°C. The sodium carbonate solution is added to the mixture in two batches while stirring. The first batch of sodium carbonate solution is added within 10 minutes, and the time interval between the two batches of sodium carbonate solution is 10-40 minutes. The remaining sodium carbonate solution is then added within 10 minutes. After the addition is completed, the mixture is kept warm for 20 minutes.

[0025] The amount of sodium carbonate solution added for the first time is 20-40% of the total amount of sodium carbonate solution, preferably 30-30.5%, and more preferably 30%. Correspondingly, the amount of sodium carbonate solution added for the second time is 60-80% of the total amount of sodium carbonate solution, preferably 69.5-70%, and more preferably 70%.

[0026] More preferably, the time interval between the two additions of sodium carbonate solution is 15 to 20 minutes.

[0027] The optimal time interval between the two additions of sodium carbonate solution is 20 minutes.

[0028] This invention does not have special requirements for the dropping rate of sodium carbonate solution, nor does it require uniform dropping.

[0029] During the complexation reaction, the main function of sodium carbonate solution is to adjust the pH of the system, allowing iron ions to form ferric hydroxide-ferric oxide nuclei. Adjusting the amount of sodium carbonate solution added will result in iron-nucleated particles of different sizes. All particles have the same ferric oxide nucleus at their center. The carbohydrates of carboxymaltodextrin surround the nucleus, forming a shell. This shell stabilizes the ferric oxide nucleus, controls the release of active iron nuclei, and maintains the particles in a suspended colloidal state within a certain range. The size of the iron nucleus determines the molecular weight of carboxymaltodextrin iron.

[0030] The core of this invention is the addition of sodium carbonate solution in two stages. By controlling the amount of sodium carbonate solution added in the first stage, the pH value of the system is adjusted to allow iron ions to begin forming ferric hydroxide-ferric oxide nuclei, which are maintained for a certain period of time (interval time) to promote the growth of iron nuclei. The second addition of sodium carbonate solution allows the carbohydrates of carboxymaltodextrin to surround the nuclei, forming a shell and creating complete carboxymaltodextrin iron molecules. This results in the final product, carboxymaltodextrin iron, achieving the target molecular weight and molecular weight distribution coefficient.

[0031] The carboxymethyl maltose iron has a weight-average molecular weight of 150,000 to 200,000 and a molecular weight distribution coefficient of 1.40 to 1.70.

[0032] Under the optimized process conditions of this invention, the weight-average molecular weight of the carboxymaltose iron is controlled between 166,000 and 175,000, consistent with the original sample.

[0033] As a preferred technical solution for the preparation method of carboxylated maltose iron of the present invention, it further includes: after the reaction is completed, the solution is successively subjected to alkali curing, acid curing, and high-temperature curing to obtain a stable carboxylated maltose iron solution, and then anhydrous ethanol is added to precipitate carboxylated maltose iron.

[0034] The alkaline curing process involves adjusting the pH of the solution to 10.5–12.0 using a 30% sodium hydroxide solution, controlling the temperature at 50–70°C, and stirring for 30 minutes.

[0035] The acid curing process involves adjusting the pH of the solution to 5.0–6.0 with 20% hydrochloric acid solution, controlling the temperature at 50–70°C, and stirring for 30 minutes.

[0036] The high-temperature curing process involves stirring at 90–100°C for 30 minutes.

[0037] The carboxylated maltodextrin solution is obtained by oxidizing maltodextrin with sodium bromide as a catalyst under alkaline conditions of pH 10.0 to 11.0 using hypochlorous acid.

[0038] Specifically, the carboxylated maltodextrin solution is prepared by the following method: maltodextrin is dissolved in 2 to 3 times its weight of water, sodium bromide at 1% to 2% of the maltodextrin mass is used as a catalyst, the pH is adjusted to 10.0 to 11.0 with 30% sodium hydroxide solution, the temperature is controlled at 25 to 40°C, and 0.4 to 0.6 times the weight of maltodextrin in 10% sodium hypochlorite solution is added under stirring to obtain the carboxylated maltodextrin solution.

[0039] The DE value of maltodextrin is 10-15.

[0040] Carboxylated maltodextrin complexes with iron ions in ferric chloride solution, and sodium carbonate solution is added according to the above process to generate carboxylated maltodextrin iron.

[0041] The beneficial effects of this invention are:

[0042] This invention incorporates practical production practices, fixing the raw material ratio, material concentration, and temperature of the reaction system, and controlling the number of times sodium carbonate solution is added, the amount added each time, and the time interval between the two additions, to obtain carboxymethyl maltose iron with the target molecular weight and molecular weight distribution.

[0043] Under the optimized process conditions of this invention, the weight-average molecular weight of carboxymaltose iron is controlled between 166,000 and 175,000, consistent with the original sample.

[0044] Compared to existing processes, the method of this invention is simple, the sodium carbonate solution addition process is short, and uniform dripping is not required. The entire reaction process is shortened to about 1 hour, and it is independent of the amount of reaction. There is no need to control the dripping rate of the sodium carbonate solution for a long time. It has low requirements for equipment and technology, greatly improves the stability and reliability of the process, and is particularly suitable for industrial operation. In actual production, it not only significantly reduces the reaction temperature, but also significantly reduces the complexation reaction time, achieving the effect of shortening the reaction cycle and saving energy. While ensuring the acquisition of carboxymethyl maltose iron with the target molecular weight and molecular weight distribution, it conforms to the trend of energy conservation and environmental protection, and has great practical significance. Detailed Implementation

[0045] The technical solution of the present invention will be further described below through specific embodiments.

[0046] Example 1

[0047] 70g of maltodextrin (DE value of 12.5, the same below) is dissolved in 170g of water by stirring. 0.7g of sodium bromide is added, and 30% sodium hydroxide solution is added to adjust the pH of the maltodextrin solution to 10.0-11.0. The temperature is controlled at 30-40℃. Under stirring, 34g of 10% sodium hypochlorite solution is added to obtain a carboxylated maltodextrin solution.

[0048] First, mix the carboxylated maltodextrin solution with the ferric chloride solution (prepared by adding 166g of water to 130g of ferric chloride hexahydrate), stir, and control the temperature at 30-40℃.

[0049] Dissolve 62g of sodium carbonate in 280g of water by stirring to obtain a sodium carbonate solution. While stirring at 30-40℃, add the sodium carbonate solution (the initial addition amount is shown in Table 1) to the mixture of carboxymethyl maltodextrin and ferric chloride. Complete the addition within 10 minutes. After the addition is complete, maintain the temperature for 20 minutes. Then add the remaining sodium carbonate solution, completing the addition within 10 minutes. After the addition is complete, maintain the temperature for 20 minutes. After the reaction was complete, the pH of the solution was adjusted to 10.5–12.0 using 30% sodium hydroxide solution, and the temperature was controlled at 50–70℃ for 30 minutes (alkali solidification). The pH of the solution was then adjusted to 5.0–6.0 using 20% ​​hydrochloric acid solution, and the temperature was controlled at 50–70℃ for 30 minutes (acid solidification). The temperature was then raised to 90–100℃ and stirred for another 30 minutes (high-temperature solidification) to obtain a stable carboxymethyl maltose iron solution. After cooling to room temperature, 240g of anhydrous ethanol was added to precipitate the carboxymethyl maltose iron. The solution was then filtered, dried, and the molecular weight was determined.

[0050] Table 1. Effect of the amount of sodium carbonate solution added initially on the molecular weight of carboxymaltose iron.

[0051]

[0052] Table 1 shows that, with other conditions fixed, adjusting only the amount of sodium carbonate solution added initially significantly affects the molecular weight parameter of carboxymaltose iron. Controlling the amount of sodium carbonate solution added initially to 30% of the total sodium carbonate solution volume resulted in the molecular weight parameter of carboxymaltose iron closest to the original drug.

[0053] Example 2

[0054] The preparation of the carboxylated maltodextrin solution is the same as in Example 1.

[0055] First, mix the carboxylated maltodextrin solution with the ferric chloride solution (prepared by adding 166g of water to 130g of ferric chloride hexahydrate), stir, and control the temperature at 30-40℃.

[0056] Dissolve 62g of sodium carbonate in 280g of water by stirring to obtain a sodium carbonate solution. Take 103g of the sodium carbonate solution, and while stirring at 30-40℃, add the sodium carbonate solution to the mixture of carboxymethyl maltodextrin and ferric chloride, completing the addition within 10 minutes. Following the time interval between the two additions of sodium carbonate solution as shown in Table 2, add the remaining sodium carbonate solution, completing the addition within 10 minutes, and keep warm for 20 minutes. After the reaction was complete, the pH of the solution was adjusted to 10.5–12.0 using 30% sodium hydroxide solution, and the temperature was controlled at 50–70℃ for 30 minutes (alkali solidification). The pH of the solution was then adjusted to 5.0–6.0 using 20% ​​hydrochloric acid solution, and the temperature was controlled at 50–70℃ for 30 minutes (acid solidification). The temperature was then raised to 90–100℃ and stirred for another 30 minutes (high-temperature solidification) to obtain a stable carboxymethyl maltose iron solution. After cooling to room temperature, 240g of anhydrous ethanol was added to precipitate the carboxymethyl maltose iron. The solution was then filtered, dried, and the molecular weight was determined.

[0057] Table 2. Effect of the time interval between two additions of sodium carbonate solution on the molecular weight of carboxymaltose iron.

[0058]

[0059] Table 2 shows that, with other conditions fixed, simply adjusting the time interval between the two additions of sodium carbonate solution significantly affects the molecular weight parameter. Maintaining a 20-minute time interval between the two additions of sodium carbonate solution resulted in a molecular weight parameter for carboxymaltose iron that was essentially consistent with the original study.

[0060] Example 3

[0061] The preparation of the carboxylated maltodextrin solution is the same as in Example 1.

[0062] First, mix the carboxylated maltodextrin solution with the ferric chloride solution (prepared by adding 166g of water to 130g of ferric chloride hexahydrate), stir, and control the temperature at 30-40℃.

[0063] Dissolve 62g of sodium carbonate in 280g of water by stirring to obtain a sodium carbonate solution. Take 103g of the sodium carbonate solution, and while stirring at 30-40℃, add the sodium carbonate solution to the mixture of carboxymethyl maltodextrin and ferric chloride, completing the addition within 10 minutes. Following the time interval between the two additions of sodium carbonate solution as shown in Table 3, add the remaining sodium carbonate solution, completing the addition within 10 minutes, and keep warm for 20 minutes. After the reaction was complete, the pH of the solution was adjusted to 10.5–12.0 using 30% sodium hydroxide solution, and the temperature was controlled at 50–70℃ for 30 minutes (alkali solidification). The pH of the solution was then adjusted to 5.0–6.0 using 20% ​​hydrochloric acid solution, and the temperature was controlled at 50–70℃ for 30 minutes (acid solidification). The temperature was then raised to 90–100℃ and stirred for another 30 minutes (high-temperature solidification) to obtain a stable carboxymethyl maltose iron solution. After cooling to room temperature, 240g of anhydrous ethanol was added to precipitate the carboxymethyl maltose iron. The solution was then filtered, dried, and the molecular weight was determined.

[0064] Table 3. Effect of the time interval between two additions of sodium carbonate solution on the molecular weight of carboxymaltose iron.

[0065]

[0066]

[0067] As shown in Table 3, under the condition that other conditions are fixed, when the time interval between the two additions of sodium carbonate solution is further refined, the molecular weight parameter of carboxymaltose iron is close to that of the original drug when the time interval is 15 to 20 minutes. In particular, when the time interval is controlled to be 20 minutes, the molecular weight parameter of carboxymaltose iron is even closer to that of the original drug.

[0068] In summary, the most preferred process of this invention is as follows: sodium carbonate solution is added to the mixture of carboxy maltodextrin solution and ferric chloride solution in two separate additions, with the amount of sodium carbonate solution added in the first addition controlled to be 30% of the total amount of sodium carbonate solution, and the time interval between the two additions of sodium carbonate solution being 20 minutes. This process can produce carboxy maltodextrin iron with a molecular weight and molecular weight distribution coefficient that are closer to those of the original carboxy maltodextrin iron.

[0069] Example 4

[0070] Dissolve 700g of maltodextrin in 1700g of water by stirring. Add 7g of sodium bromide and adjust the pH of the maltodextrin solution to 10.0-11.0 with 30% sodium hydroxide solution. Control the temperature at 30-40℃. Add 340g of 10% sodium hypochlorite solution while stirring to obtain a carboxylated maltodextrin solution.

[0071] First, mix the carboxylated maltodextrin solution with the ferric chloride solution (prepared by adding 1660g of water to 1300g of ferric chloride hexahydrate), stir, and control the temperature at 30-40℃.

[0072] Dissolve 620g of sodium carbonate in 2800g of water by stirring to obtain a sodium carbonate solution. Take 1030g of the sodium carbonate solution, control the temperature at 30-40℃, and add the sodium carbonate solution to the mixture of carboxymethyl maltodextrin and ferric chloride while stirring. Add the sodium carbonate solution within 10 minutes. After the addition is complete, keep the temperature for 20 minutes, then add the remaining sodium carbonate solution within 10 minutes, and keep the temperature for another 20 minutes. After the reaction was complete, the pH of the solution was adjusted to 10.5–12.0 using 30% sodium hydroxide solution, and the temperature was controlled at 50–70℃ for 30 minutes (alkali solidification). The pH of the solution was then adjusted to 5.0–6.0 using 20% ​​hydrochloric acid solution, and the temperature was controlled at 50–70℃ for 30 minutes (acid solidification). The temperature was then raised to 90–100℃ and stirred for another 30 minutes (high-temperature solidification) to obtain a stable carboxymethyl maltose iron solution. After cooling to room temperature, 2400g of anhydrous ethanol was added to precipitate the carboxymethyl maltose iron. The solution was then filtered, dried, and a carboxymethyl maltose iron sample was taken. The molecular weight was determined to be 169,581 (weight average), 104,680 (number average), and 1.62 (molecular weight distribution coefficient).

[0073] This indicates that under the optimized process conditions of this invention, even with a 10-fold increase in experimental quantity, the molecular weight data of carboxymaltose iron remained stable.

[0074] Example 5

[0075] Dissolve 10,000g of maltodextrin in 25,000g of water by stirring. Add 100g of sodium bromide and adjust the pH of the maltodextrin solution to 10.0-11.0 with 30% sodium hydroxide solution. Control the temperature at 30-40℃. Add 4860g of 10% sodium hypochlorite solution while stirring to obtain a carboxylated maltodextrin solution.

[0076] The carboxylated maltodextrin solution and the ferric chloride solution (prepared by mixing 18570g of ferric chloride hexahydrate with 23700g of water) are first mixed and stirred, and the temperature is controlled at 30-40℃.

[0077] Dissolve 8860g of sodium carbonate in 40000g of water by stirring to obtain a sodium carbonate solution. Take 14660g of the sodium carbonate solution, control the temperature at 30-40℃, and add the sodium carbonate solution to the mixture of carboxymethyl maltodextrin and ferric chloride while stirring. Add the 14660g sodium carbonate solution within 10 minutes. After the addition is complete, keep the temperature for 20 minutes, then add the remaining sodium carbonate solution within 10 minutes, and keep the temperature for another 20 minutes. After the reaction was complete, the pH of the solution was adjusted to 10.5–12.0 using 30% sodium hydroxide solution, and the temperature was controlled at 50–70℃ for 30 minutes (alkali solidification). The pH of the solution was then adjusted to 5.0–6.0 using 20% ​​hydrochloric acid solution, and the temperature was controlled at 50–70℃ for 30 minutes (acid solidification). The temperature was then raised to 90–100℃ and stirred for another 30 minutes (high-temperature solidification) to obtain a stable carboxymethyl maltose iron solution. After cooling to room temperature, 34,300 g of anhydrous ethanol was added to precipitate the carboxymethyl maltose iron. The solution was then filtered, dried, and a carboxymethyl maltose iron sample was taken. The molecular weight was determined to be 168,798 (weight average), 104,996 (number average), and 1.61 (molecular weight distribution coefficient).

[0078] The amount of material fed in this embodiment has reached the production scale. It can be seen that, under the process conditions of the present invention, the molecular weight data of the sample is basically consistent with that of the small batch of material-fed samples and the original research samples, indicating that the process of the present invention is stable and meets the requirements of actual production.

Claims

1. A process for the preparation of carboxymaltose iron, characterized in that: include: Sodium carbonate solution was added to the mixture of carboxylic maltodextrin solution and ferric chloride solution in two separate additions. The amount of sodium carbonate solution added in the first addition was controlled to be 20-40% of the total amount of sodium carbonate solution, and the time interval between the two additions of sodium carbonate solution was 10-40 minutes. Carboxylic maltodextrin iron with target molecular weight and molecular weight distribution coefficient was obtained. The weight ratio of carboxylated maltodextrin (calculated as raw material maltodextrin) to ferric chloride (calculated as ferric chloride hexahydrate) is 7:

13. The DE value of maltodextrin is 10-15; The concentration of ferric chloride in the ferric chloride solution is 25-30% (w / w); The concentration of sodium carbonate in the sodium carbonate solution is 15-25% (w / w). The carboxymethyl maltose iron has a weight-average molecular weight of 150,000 to 200,000 and a molecular weight distribution coefficient of 1.40 to 1.

70.

2. The process for the preparation of carboxymaltose iron according to claim 1, characterized in that: Based on ferric chloride hexahydrate, the weight ratio of ferric chloride to sodium carbonate is 2:1 to 3:

1.

3. The process for the preparation of carboxymaltose iron according to claim 1, characterized in that: First, mix the carboxymethyl maltodextrin solution and ferric chloride solution evenly, and control the temperature at 30-40℃. Add sodium carbonate solution to the mixture in two batches while stirring. Add the sodium carbonate solution in the first batch within 10 minutes, with an interval of 10-40 minutes between the two additions. Then add the remaining sodium carbonate solution within 10 minutes. After the addition is complete, keep the mixture warm for 20 minutes.

4. The process for the preparation of carboxymaltose iron according to claim 1, characterized in that: The amount of sodium carbonate solution added for the first time should be 30 to 30.5% of the total amount of sodium carbonate solution.

5. The process for the preparation of carboxymaltose iron according to claim 4, characterized in that: The amount of sodium carbonate solution added for the first time is 30% of the total amount of sodium carbonate solution.

6. The method for preparing carboxylated maltose iron according to claim 1 or 3, characterized in that: The time interval between the two additions of sodium carbonate solution is 15 to 20 minutes.

7. The method for preparing carboxylated maltose iron according to claim 6, characterized in that: The time interval between the two additions of sodium carbonate solution is 20 minutes.

8. The method for preparing carboxylated maltose iron according to claim 1, characterized in that: The carboxylated maltodextrin solution is obtained by oxidizing maltodextrin with sodium bromide as a catalyst under alkaline conditions of pH 10.0 to 11.0 using hypochlorous acid.

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