A method for preparing sucrose iron and its application

Abstract

This invention provides a method for preparing sucrose iron and its application. Ferric hydroxide is prepared at 1–5°C using ferric nitrate nonahydrate as a raw material, with the pH adjusted to 3.5–4.0 using alkali. At 10–20°C, the ferric hydroxide is added to 95% ethanol, and sucrose is added at a molar ratio of (3–6):1 to ferric nitrate nonahydrate. After the reaction is complete, the solvent is removed by vacuum distillation. 95% ethanol and a water-insoluble organic solvent are added to the residue, and after thorough stirring and cooling, the sucrose iron is purified using the water-insoluble organic solvent and then vacuum dried below 55°C. The sucrose iron prepared by this method has high purity, a narrow weight-average molecular weight distribution, and higher stability and safety. The entire synthesis method is simple and cost-effective. The sucrose iron prepared by this method can be used in the preparation of sucrose iron injection or sucrose powder injection.

Description

Technical Field

[0001] This invention relates to the preparation and application of an iron-containing pharmaceutical composition, and particularly to the preparation and application of sucrose iron. Background Technology

[0002] Sucrose iron is prepared by complexing ferric hydroxide colloid with sucrose. It is a water-soluble ferric hydroxide-sucrose complex in which the iron is in a non-ionic state. In the molecule, the ferric hydroxide colloid forms a polynuclear iron core, while sucrose binds to the iron core by replacing water molecules on its surface through its active hydroxyl groups. The binding force between the two is a non-covalent intermolecular force. This polynuclear ferric hydroxide core is lightly surrounded by a large number of non-covalent sucrose molecules, thus forming a large molecular complex. The structure of this multinuclear iron complex is similar to that of naturally occurring ferritin.

[0003] CN103059072B discloses a green and environmentally friendly method for preparing sucrose iron raw material. Ferric chloride hexahydrate reacts with sodium carbonate solution to generate ferric hydroxide. The ferric hydroxide then reacts with sucrose at 85–140℃ and pH 8–13 to obtain a crude sucrose iron solution. This crude solution is sequentially treated with a D301 type anion exchange resin and a D113 type cation exchange resin, and the pH is adjusted to 10.2–11.0. Ultrafiltration is then performed using a 0.8 μm filter membrane to obtain a purified sucrose iron solution. The weight-average molecular weight of the prepared sucrose iron is 34,000–60,000 Da. This method uses ion exchange resins to purify the product. When the ion exchange resin reaches saturation, it needs to be regenerated. Therefore, in industrial production, this method requires ion exchange resin regeneration equipment and reagents, and at least two sets of ion exchange resins need to be used alternately to ensure continuous production, making the operation more cumbersome and increasing production costs.

[0004] CN104098616B discloses a method for preparing sucrose iron. Sucrose is added to a 20-50% sodium hydroxide solution and stirred at 50-80°C for 0.5-1.5 hours. The solution is then cooled to room temperature and the pH is adjusted to 2-4 with hydrochloric acid. The solution is heated to 90-110°C, and under constant temperature conditions, ferric chloride and sodium hydroxide are added dropwise for a complexation reaction for 3-5 hours. The solution is then cooled to 50-70°C, and sodium hydroxide is added to adjust the pH to 10.5-11.1, maintaining this temperature for 0.5-2 hours. The resulting sucrose iron solution is filtered using a microfiltration machine, and then filtered again at 1.0-4.0 MPa using a nanofiltration membrane to retain the sucrose iron complex with a molecular weight cutoff of 200-1000 Da. The nanofiltration solution is then filtered through a 0.2-0.45 μm microfiltration membrane and sterilized at 100-120°C for 20-40 minutes to obtain the final product. The molecular weight of sucrose iron prepared by this method does not meet the requirements for sucrose iron molecular weight in USP40 (United States Pharmacopeia 40th Edition).

[0005] Existing literature reports that the toxicity of sucrose iron complexes is related to molecular weight and molecular stability (see Fishbane et al., Semin Dial. 2000 Nov-Dec; 13(6):3814.). The molecular weight of sucrose iron prepared using existing technologies is concentrated between 34,000 and 60,000 Da, showing a wide molecular weight distribution. Although generally stable, it requires very strict storage and transportation conditions. The FDA-approved Venofer injection package insert clearly states that it should be stored at 20–25°C, with permissible fluctuations between 15 and 30°C, and should not be frozen. The package insert for commercially available Venofer also states that improper storage can lead to the formation of visible precipitates. Therefore, a new method for synthesizing sucrose iron is needed to control its molecular weight distribution, thereby improving its safety and stability. Summary of the Invention

[0006] To prepare sucrose iron with suitable molecular weight, better stability, and improved safety, while simplifying the operation steps and reducing production costs, this invention provides a method for preparing sucrose iron. The sucrose iron synthesized by this method has high purity, with a weight-average molecular weight controlled between 50,000 and 55,000 Da. The organic solvent used is easily recyclable, and the entire synthesis process is simple. To achieve the above objectives, the technical solution adopted by this invention includes the following steps:

[0007] S1: At 1-5℃, dissolve ferric nitrate nonahydrate in deionized water, add alkali to adjust the pH of the solution to 3.5-4.0, let the reaction mixture stand for 10-30 minutes after the reaction is complete, then filter, wash the filter cake with deionized water until the pH is 7.0-7.5, and use the obtained ferric hydroxide filter cake for later use.

[0008] S2: At 10-20°C, the ferric hydroxide prepared in step S1 is added to 95% ethanol. Under stirring, sucrose is added within 60-75 minutes. The molar ratio of sucrose to ferric nitrate nonahydrate in step S1 is (3-6):1. After the reaction is complete, the solvent is removed by vacuum distillation. 95% ethanol and an organic solvent insoluble in water are added to the residue. The mixture is cooled to 10-20°C and stirred for 1-1.5 hours to obtain a crude sucrose-iron mixture.

[0009] S3: Add the water-insoluble organic solvent to the crude sucrose iron mixture, stir at 10-20°C for 1-2 hours, and then vacuum filter; wash the filter cake with the water-insoluble organic solvent and filter again, and then vacuum dry at below 55°C to obtain the sucrose iron complex.

[0010] The temperature and pH value of ferric hydroxide synthesis in step S1 have a significant impact on the yield and purity of sucrose iron synthesis in step S2. Too high or too low a reaction temperature will affect the purity and yield of ferric hydroxide, thus affecting the purity and yield of sucrose iron. Too low a pH value results in a low yield of ferric hydroxide, which in turn reduces the yield of sucrose iron. While increasing the pH value will improve the yield of ferric hydroxide, excessively high pH values ​​will hinder the reaction between ferric hydroxide and sucrose, leading to insufficient sucrose utilization and consequently a low yield of sucrose iron. This invention achieves optimal synergy between reaction steps by strictly controlling the reaction conditions of each step. Furthermore, step S2 of this invention does not require the second pH adjustment step found in the prior art, nor does it require reaction under high temperature conditions. Instead, ferric hydroxide and sucrose react in an organic solvent system containing a small amount of water. Finally, in step S3, an organic solvent insoluble in water is used to purify the product, thereby controlling the molecular weight distribution of sucrose iron within a narrow range. This results in higher stability and safety compared to sucrose iron prepared in the prior art, which has a too wide molecular weight distribution.

[0011] Preferably, the alkali in step S1 is one of sodium carbonate, sodium hydroxide, sodium bicarbonate, ammonia, and ethylenediamine, or a mixture of any two of them.

[0012] Preferably, in step S2, the molar ratio of sucrose to ferric nitrate nonahydrate is (4-5):1.

[0013] Preferably, the water-insoluble organic solvent in step S2 is any one of ethyl acetate, toluene, methyl tert-butyl ether, cyclohexane, and dichloromethane.

[0014] Choosing an organic solvent that is insoluble in water to precipitate the product helps improve the purity of sucrose iron and control its molecular weight. It also simplifies the subsequent organic solvent recovery process and reduces production costs.

[0015] Preferably, the vacuum drying temperature in step S3 is 30–50°C.

[0016] Preferably, the sucrose iron prepared according to any one of the above preparation methods has a weight-average molecular weight of 50,000 to 55,000 Da.

[0017] Preferably, the sucrose iron prepared according to any one of the above preparation methods is used in the preparation of sucrose iron injection or sucrose powder injection.

[0018] The beneficial effects of this invention are: strict control of the reaction conditions in the synthesis of ferric hydroxide; the synthesis of sucrose iron is carried out in an organic solvent containing a small amount of water, eliminating the need for pH adjustment and high-temperature reaction; and the final separation and purification of sucrose iron using an organic solvent, resulting in sucrose iron prepared by this invention having high purity and a narrow molecular weight distribution of 50,000–55,000 Da, exhibiting higher safety and better stability; and simple operation in industrial production, with the solvent capable of being recycled. Detailed Implementation

[0019] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Any equivalent modifications or substitutions made by those skilled in the art based on the following embodiments are within the scope of protection of the present invention.

[0020] Example 1

[0021] S1: At 5±0.5℃, dissolve 7.5g of ferric nitrate nonahydrate in 30mL of deionized water. While stirring, add 25% ammonia solution dropwise to the solution, monitoring the pH value of the mixed solution. Stop adding 25% ammonia solution when the pH value of the solution reaches 4.0. Let the mixture stand for 30min after the reaction is complete, then filter it. Wash the filter cake with deionized water until the pH value reaches 7.0-7.5. The obtained ferric hydroxide filter cake is ready for use.

[0022] S2: At 15±0.5℃, the ferric hydroxide prepared in step S1 was added to 40mL of 95% ethanol. While stirring, 31.7g of sucrose (i.e., the molar ratio of sucrose to ferric nitrate nonahydrate was 5:1) was added over 60–75 min. After the reaction was complete, the solvent was removed by vacuum distillation. 30mL of a mixed solvent of 95% ethanol and cyclohexane (volume ratio of 95% ethanol to cyclohexane was 1:2) was added to the residue. The mixture was then cooled to 15±0.5℃ and stirred for 1.5h to obtain a crude sucrose-iron mixture. A 1mL sample was tested, and the purity of the obtained product was greater than 98.5%, with a weight-average molecular weight of 55000 Da.

[0023] S3: Add 50 mL of cyclohexane to the crude sucrose-iron mixture obtained in step 2, stir at 15 ± 0.5 °C for 1 hour, then let stand for 20 min. Filter the reaction mixture under vacuum. Wash the filter cake twice with 50 mL of cyclohexane, filtering under vacuum after each wash. Combine the filtrates from the three filtrations and recover the solvent. Finally, vacuum dry the filter cake at 40 °C to obtain the sucrose-iron complex.

[0024] Example 2

[0025] The difference between this embodiment and Example 1 is that the pH value in step S1 is 3.5. After the reaction in step S2 is completed, a sample is taken for testing, and the purity of the obtained sucrose iron is greater than 98.0%, with a weight-average molecular weight of 53600 Da.

[0026] Example 3

[0027] The difference between this embodiment and Example 1 is that the water-insoluble organic solvent in steps S2 and S3 is methyl tert-butyl ether. After the reaction in step S2 is completed, a sample was taken for testing, and the purity of the obtained sucrose iron was greater than 98.5%, with a weight-average molecular weight of 51800 Da.

[0028] Example 4

[0029] The difference between this embodiment and Embodiment 1 is that the reaction temperature in step S1 is 1 ± 0.5℃. After the reaction in step S2 is completed, a sample is taken for testing, and the purity of the obtained sucrose iron is greater than 97.0%, with a weight-average molecular weight of 50,000 Da.

[0030] Example 5

[0031] The difference between this embodiment and Embodiment 1 is that the amount of sucrose used in step S2 is 25.3g (i.e., the molar ratio of sucrose to ferric nitrate nonahydrate is 4:1). After the reaction in step S2 is completed, a sample is taken for testing, and the purity of the obtained sucrose iron is greater than 97.0%, with a weight-average molecular weight of 54200 Da.

[0032] Example 6

[0033] The difference between this embodiment and Example 1 is that the water-insoluble organic solvent in steps S2 and S3 is ethyl acetate. After the reaction in step S2 was completed, a sample was taken for testing, and the purity of the obtained sucrose iron was greater than 97.5%, with a weight-average molecular weight of 51300 Da.

[0034] Comparative Example 1

[0035] The difference between this comparative example and Example 1 is that the pH value was adjusted to 5.0 with alkali in step S1. After the reaction in step S2 was completed, a sample was taken for testing, and the purity of the obtained sucrose iron was 97.5%, and the weight-average molecular weight was 59800 Da.

[0036] Comparative Example 2

[0037] The difference between this comparative example and Example 1 is that the reaction temperature in step S1 is 10 ± 0.5 °C. After the reaction in step S2 is completed, a sample was taken for testing, and the purity of the obtained sucrose iron was 95.0%, and the weight-average molecular weight was 78200 Da.

[0038] Comparative Example 3

[0039] The difference between this comparative example and Example 1 is that the reaction temperature in step S1 is 10℃±0.5℃, and the pH value is adjusted to 2.5. After the reaction in step S2 is completed, a sample is taken for testing, and the purity of the obtained sucrose iron is 95.0%, and the weight-average molecular weight is 44700 Da.

[0040] Comparative Example 4

[0041] The steps for preparing sucrose iron in this comparative example are as follows:

[0042] S1: At 5±0.5℃, dissolve 7.5g of ferric nitrate nonahydrate in 30mL of deionized water. While stirring, add 25% ammonia solution dropwise to the solution, monitoring the pH value of the mixed solution. Stop adding 25% ammonia solution when the pH value of the solution reaches 4.0. Let the mixture stand for 30min after the reaction is complete, then filter it. Wash the filter cake with deionized water until the pH value reaches 7.0-7.5, and then disperse the filter cake in 25mL of deionized water to obtain a ferric hydroxide suspension.

[0043] S2: At 15±0.5℃, dissolve 31.7g of sucrose in 16mL of deionized water, add 25% ammonia to adjust the pH to 9.5, and then slowly add the ferric hydroxide suspension prepared in step S1 to the solution, controlling the addition time to within 30min. Heat the reaction mixture to 95℃ and maintain this temperature for 3.5 hours. After the reaction is complete, cool the mixture to 15℃. Take 1mL of sample for testing; the purity of the obtained product is greater than 96.5%, and the weight-average molecular weight is 89000Da.

[0044] S3: At 25±0.5℃, add 200mL of ethanol to the mixture after the reaction in step S2 under stirring, continue stirring for 30min, let stand for 10min, filter, wash the filter cake twice with 100mL of ethanol and filter again, and vacuum dry the obtained filter cake at 40℃ to obtain sucrose iron complex.

[0045] sucrose iron stability test

[0046] Following the method for preparing sucrose iron injection in CN103340827B, sucrose iron prepared in Examples 1, 4, Comparative Examples 1, 2, and 3 was used to prepare sucrose iron injection. The five samples were tested using the light inspection method in General Chapter 0904 (Visible Foreign Matter Inspection Method) of the 2020 edition of the Chinese Pharmacopoeia. The turbidity of the five samples was then tested according to the turbidity test method for sucrose iron injection in USP40. After the five samples were treated with the hot and cold cycling method in CN103340827B, the visible foreign matter and turbidity of the samples were retested. The test results are shown in Table 1.

[0047] Table 1. Stability test of sucrose iron

[0048]

[0049] Based on the above test results, it can be seen that in Comparative Example 2, the stability of sucrose iron deteriorated when the molecular weight was too large, and the initial turbidity test result was unqualified. Although the molecular weight range of sucrose iron in Comparative Examples 1 and 3 was within the range specified in USP40, its stability was not as good as that of the sucrose iron prepared in the embodiments of this invention. Therefore, it is evident that when reaction conditions are not strictly controlled, the synthesized sucrose iron has a wide molecular weight distribution, its turbidity varies greatly with environmental influences, and its stability is poor. In contrast, this invention strictly controls the reaction conditions of each reaction step, thereby resulting in a narrower molecular weight distribution and significantly improved stability of the synthesized sucrose iron.

[0050] The above description is merely a preferred embodiment of the present invention and is not intended to limit the scope of protection of the present invention. Various modifications and variations can be made to the present invention by any person skilled in the art. Any simple equivalent changes and modifications made based on the scope of protection of the present invention and the content of the specification should be included within the scope of protection of the present invention.

Claims

1. A method for preparing sucrose iron, characterized in that, The method includes the following steps: S1: At 1~5℃, ferric nitrate nonahydrate is dissolved in deionized water. An alkali is added to the solution to adjust the pH to 3.5~4.

0. After the reaction is complete, the reaction mixture is allowed to stand for 10~30 minutes, then filtered. The filter cake is washed with deionized water until the pH reaches 7.0~7.

5. The resulting ferric hydroxide filter cake is then used for later use. The alkali is ammonia water. S2: At 10~20℃, add the ferric hydroxide prepared in step S1 to 95% ethanol, and add sucrose within 60~75 min while stirring. The molar ratio of sucrose to ferric nitrate nonahydrate in step S1 is (3~6):

1. After the reaction is completed, remove the solvent by vacuum distillation, add 95% ethanol and water-insoluble organic solvent to the residue, cool to 10~20℃, and stir for 1~1.5 h to obtain a crude sucrose iron mixture. S3: Add the water-insoluble organic solvent to the crude sucrose iron mixture obtained in step S2, stir at 10~20℃ for 1~2 hours, let stand, and then vacuum filter; wash the filter cake with the water-insoluble organic solvent and filter again, and then vacuum dry at below 55℃ to obtain the sucrose iron complex; the weight average molecular weight of the sucrose iron is 50000~55000 Da.

2. The preparation method according to claim 1, characterized in that, In step S2, the molar ratio of sucrose to ferric nitrate nonahydrate is (4~5):

1.

3. The preparation method according to claim 1, characterized in that, The water-insoluble organic solvent mentioned in step S2 is any one of ethyl acetate, toluene, methyl tert-butyl ether, cyclohexane, and dichloromethane.

4. The preparation method according to claim 1, characterized in that, The temperature for vacuum drying in step S3 is 30~50℃.

5. The application of sucrose iron prepared by the preparation method according to any one of claims 1 to 4 in the preparation of sucrose iron injection or sucrose powder injection.

Images