Preparation method of citric acid ferric pyrophosphate

Abstract

The invention relates to the technical field of medicine synthesis, and particularly discloses a preparation method of citric acid ferric pyrophosphate. According to the preparation method of the citric acid ferric pyrophosphate, the dissolution rate of ferric sulfate is increased by utilizing trace ferrous sulfate, the operation of high-temperature treatment in the preparation process is reduced, the technological process of the citric acid ferric pyrophosphate is greatly simplified, the production cost is reduced, and the citric acid ferric pyrophosphate prepared by the method is high in purity and stable in quality. By utilizing the technical scheme of the invention, the problems of high production cost, complicated operation, long time consumption and low purity of the obtained product in the existing method for synthesizing citric acid ferric pyrophosphate are effectively solved, and a new thought is provided for the preparation of citric acid ferric pyrophosphate.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and particularly relates to a preparation method of ferric pyrophosphate citrate. Background Art

[0002] Ferric pyrophosphate citrate is an iron supplement that can effectively increase the iron concentration in the blood, promote the synthesis of hemoglobin, and alleviate anemia symptoms by improving iron absorption. Ferric pyrophosphate citrate is mainly applicable to the treatment of iron deficiency anemia caused by the following diseases: (1) anemia caused by chronic kidney disease; (2) anemia related to non-dialysis-dependent chronic kidney disease; (3) anemia caused by insufficient iron intake or poor absorption. More importantly, ferric pyrophosphate citrate can effectively reduce gastrointestinal irritation and other potential drug interactions.

[0003] However, in the preparation process of ferric pyrophosphate citrate, the dissolution operation is relatively difficult and the synthesis cycle is relatively long, resulting in relatively high production costs. There is a reported disclosure of a ferric pyrophosphate citrate pharmaceutical composition for the treatment of iron deficiency anemia, and this pharmaceutical composition is administered orally or by injection. However, the route adopted in this report requires heating citrate, pyrophosphate and ferric sulfate, and the above three substances are unstable under heating conditions. Under heating conditions, iron ions in ferric sulfate are prone to hydrolysis to produce ferric hydroxide colloid; pyrophosphate has thermal instability and is prone to degradation to produce phosphate impurities under heating conditions; citrate also degrades to produce various organic impurities under the above preparation process, such as formic acid, oxalic acid, cis / trans aconitic acid or other acid radicals. Therefore, the characteristics of these three raw materials affect the dissolution rate and purity of ferric pyrophosphate citrate, and further affect the bioavailability of ferric pyrophosphate citrate. There is also a reported disclosure of a preparation method of ferric pyrophosphate citrate. First, ferric sulfate, sodium citrate and sodium pyrophosphate are dissolved separately, then the sodium pyrophosphate solution is slowly added to the sodium citrate solution, and finally the ferric sulfate solution is added. After mixing evenly, it is filtered to remove insoluble substances. The filtrate is added dropwise to the crystallization solvent and stirred for a period of time to obtain a light green precipitate, which is dried to obtain a ferric pyrophosphate citrate complex. However, the preparation process adopted in this report is too cumbersome and time-consuming; there is also a reported disclosure of a preparation method of ferric pyrophosphate citrate. Sodium citrate, sodium pyrophosphate and hydrated ferric sulfate are mixed evenly and dissolved, and then the crystallization solvent is added dropwise to the mixed solution to gradually produce a light green precipitate. After stirring and crystal cultivation, it is filtered under reduced pressure and dried to obtain a ferric pyrophosphate citrate product. However, the amount of water used in this route is large, which is 20 times the amount of ferric sulfate used, and the amount of crystallization solvent used is 3-5 times the volume of the reaction solution. The large amount of crystallization solvent used results in high costs and is not conducive to industrial production. There is also a reported disclosure of a new preparation method of ferric pyrophosphate citrate. After adding sulfuric acid and hydrated ferric sulfate to a reaction flask and dissolving, sodium citrate is added. After stirring and dissolving, sodium pyrophosphate is added, and it is dissolved by water bath insulation. The above mixed solution is added dropwise to ethanol under stirring to produce a light green precipitate, which is filtered. The filter cake is redissolved, and the pH is adjusted with sodium bicarbonate to obtain a redissolved solution, and then it is crystallized in ethanol and dried to obtain a ferric pyrophosphate citrate product. However, the amount of crystallization solvent used in this route is large, and sulfuric acid and sodium bicarbonate are required, resulting in increased production costs and complex operations. At the same time, it is easy to cause residues of sulfate and sodium ions, affecting the purity of ferric pyrophosphate citrate.

[0004] Based on this, it is of important practical significance to develop a process route for ferric pyrophosphate citrate that is green and environmentally friendly, simple to operate, has a high yield and low cost. Summary of the Invention

[0005] In view of the problems existing in the existing methods for synthesizing ferric citrate pyrophosphate, such as high production cost, complex operation, long time consumption and low purity of the obtained product, the present invention provides a preparation method of ferric citrate pyrophosphate, which not only simplifies the production steps of ferric citrate pyrophosphate, greatly shortens the preparation process, reduces the production cost, but also has high purity and stable quality of the ferric citrate pyrophosphate prepared by using the technical solution of the present invention, which is beneficial to industrial production.

[0006] To achieve the above invention purpose, the present invention provides the following technical solutions: The first aspect of the present invention provides a preparation method of ferric citrate pyrophosphate, comprising the following steps: Step 1: Dissolve ferrous sulfate in deionized water to obtain a ferrous sulfate solution; add ferric sulfate to the ferrous sulfate solution, and stir at 35-45 °C for 3-5 h to obtain a ferric sulfate solution; add sodium citrate to the ferric sulfate solution and mix evenly to obtain a first reaction solution; Step 2: Add sodium pyrophosphate to the first reaction solution to obtain a second reaction solution; Step 3: Add the second reaction solution to a crystallization solvent for crystallization to obtain ferric citrate pyrophosphate; Wherein, the mass ratio of ferrous sulfate to ferric sulfate is 3:97-0.5:99.5; the concentration of the ferric sulfate solution is 0.1 mol / L-0.4 mol / L.

[0007] Compared with the prior art, the present invention first dissolves a trace amount of ferrous sulfate in deionized water to obtain a ferrous sulfate solution, and then dissolves ferric sulfate with the ferrous sulfate solution. The inventor has found through a large number of creative experiments that a trace amount of ferrous sulfate can accelerate the dissolution rate of ferric sulfate. Moreover, the present invention limits the concentration of the ferric sulfate solution. At a lower concentration, the presence of divalent iron ions will inhibit the hydrolysis of trivalent iron ions, which is beneficial to the dissolution of trivalent iron ions, resulting in an accelerated dissolution rate of ferric sulfate. In addition, the preparation method provided by the present invention does not involve high-temperature dissolution, which can effectively avoid the degradation of sodium citrate and sodium pyrophosphate in the raw materials, reduce the generation of impurities, and ensure the purity of ferric citrate pyrophosphate.

[0008] Preferably, the mass ratio of ferrous sulfate to ferric sulfate is 2:98-0.5:99.5.

[0009] Preferably, the molar ratio of ferric sulfate to sodium citrate is 1:1.5-1:2.5.

[0010] Preferably, the molar ratio of ferric sulfate to sodium pyrophosphate is 1:1-1:1.2.

[0011] Preferably, the mass ratio of ferric sulfate to the crystallization solvent is 1:2.5-1:3.5.

[0012] Further preferably, the mass ratio of ferric sulfate to the crystallization solvent is 1:3.

[0013] The amount of the crystallization solvent used in this process is only 3 times the mass ratio of the iron salt, which greatly reduces the production cost and is beneficial to industrial production.

[0014] Preferably, the crystallization solvent is anhydrous methanol.

[0015] Preferably, the crystallization temperature is 20°C - 40°C, and the crystallization time is 1h - 3h.

[0016] Preferably, the drying temperature is 45°C - 55°C, and the drying time is 7h - 10h.

[0017] In summary, the present invention provides a preparation method of ferric citrate pyrophosphate, which uses a small amount of ferrous sulfate to accelerate the dissolution rate of ferric sulfate, reduces the operation of high-temperature treatment in the preparation process, greatly simplifies the process flow of ferric citrate pyrophosphate, reduces the production cost, and the ferric citrate pyrophosphate prepared by the present invention has high purity and stable quality. The technical solution of the present invention effectively solves the problems of high production cost, complex operation, long time consumption and low purity of the product in the existing method for synthesizing ferric citrate pyrophosphate. Specific Embodiments

[0018] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0019] Example 1 This example provides a preparation method of ferric citrate pyrophosphate, which specifically includes the following contents: Step 1: Dissolve 1 g of ferrous sulfate in 150 g of deionized water to obtain a ferrous sulfate solution; add 48.35 g of ferric sulfate nonahydrate to the ferrous sulfate solution, stir at 38°C for 4 h to obtain a ferric sulfate solution, and add 58.8 g of sodium citrate dihydrate to the ferric sulfate solution, mix evenly to obtain a first reaction solution; Step 2: Add 44.6 g of sodium pyrophosphate to the first reaction solution, stir for 2 h, dissolve, filter to obtain a second reaction solution; Step 3: Add the second reaction solution to 150 g of anhydrous methanol, perform crystallization at 35°C for 2 h, filter, and dry the filter cake at 50°C for 8 h to obtain 132.2 g of ferric citrate pyrophosphate.

[0020] Example 2 This embodiment provides a preparation method of ferric pyrophosphate citrate, which specifically includes the following content: Step 1: Dissolve 1 g of ferrous sulfate in 150 g of deionized water to obtain a ferrous sulfate solution; add 48.35 g of ferric sulfate nonahydrate to the ferrous sulfate solution, stir at 38 °C for 4 h to obtain a ferric sulfate solution, add 58.8 g of sodium citrate dihydrate to the ferric sulfate solution, and mix evenly to obtain a first reaction solution; Step 2: Add 53.5 g of sodium pyrophosphate to the first reaction solution, stir for 2 h, dissolve, filter, and obtain a second reaction solution; Step 3: Add the second reaction solution to 140 g of anhydrous methanol, perform crystallization at 35 °C for 2 h, filter, and dry the filter cake at 55 °C for 7 h to obtain 131.1 g of ferric pyrophosphate citrate.

[0021] Example 3 This embodiment provides a preparation method of ferric pyrophosphate citrate, which specifically includes the following content: Step 1: Dissolve 1 g of ferrous sulfate in 150 g of deionized water to obtain a ferrous sulfate solution; add 48.35 g of ferric sulfate nonahydrate to the ferrous sulfate solution, stir at 38 °C for 4 h to obtain a ferric sulfate solution, add 58.8 g of sodium citrate dihydrate to the ferric sulfate solution, and mix evenly to obtain a first reaction solution; Step 2: Add 44.6 g of sodium pyrophosphate to the first reaction solution, stir for 2 h, dissolve, filter, and obtain a second reaction solution; Step 3: Add the second reaction solution to 160 g of anhydrous methanol, perform crystallization at 38 °C for 2 h, filter, and dry the filter cake at 52 °C for 8 h to obtain 132.7 g of ferric pyrophosphate citrate.

[0022] Example 4 This embodiment provides a preparation method of ferric pyrophosphate citrate, which specifically includes the following content: Step 1: Dissolve 1 g of ferrous sulfate in 150 g of deionized water to obtain a ferrous sulfate solution; add 48.35 g of ferric sulfate nonahydrate to the ferrous sulfate solution, stir at 38 °C for 4 h to obtain a ferric sulfate solution, add 58.8 g of sodium citrate dihydrate to the ferric sulfate solution, and mix evenly to obtain a first reaction solution; Step 2: Add 45.9 g of sodium pyrophosphate to the first reaction solution, stir for 2 h, dissolve, filter, and obtain a second reaction solution; Step 3: Add the second reaction solution to 170 g of anhydrous methanol, perform crystallization at 35 °C for 2.5 h, filter, and dry the filter cake at 48 °C for 9 h to obtain 132.2 g of ferric pyrophosphate citrate.

[0023] Example 5 This example provides a preparation method of ferric pyrophosphate citrate, which specifically includes the following contents: Step 1: Dissolve 1 g of ferrous sulfate in 150 g of deionized water to obtain a ferrous sulfate solution; add 48.35 g of ferric sulfate nonahydrate to the ferrous sulfate solution, stir at 38 °C for 4 h to obtain a ferric sulfate solution, add 58.8 g of sodium citrate dihydrate to the ferric sulfate solution, and mix evenly to obtain a first reaction solution; Step 2: Add 48.7 g of sodium pyrophosphate to the first reaction solution, stir for 2 h, dissolve, filter, and obtain a second reaction solution; Step 3: Add the second reaction solution to 155 g of anhydrous methanol, perform crystallization at 40 °C for 1.5 h, filter, and dry the filter cake at 45 °C for 10 h to obtain 132.2 g of ferric pyrophosphate citrate.

[0024] Example 6 This example provides a preparation method of ferric pyrophosphate citrate, which specifically includes the following contents: Step 1: Dissolve 1 g of ferrous sulfate in 150 g of deionized water to obtain a ferrous sulfate solution; add 48.35 g of ferric sulfate nonahydrate to the ferrous sulfate solution, stir at 38 °C for 4 h to obtain a ferric sulfate solution, add 58.8 g of sodium citrate dihydrate to the ferric sulfate solution, and mix evenly to obtain a first reaction solution; Step 2: Add 44.6 g of sodium pyrophosphate to the first reaction solution, stir for 2 h, dissolve, filter, and obtain a second reaction solution; Step 3: Add the second reaction solution to 150 g of anhydrous methanol, perform crystallization at 35 °C for 3 h, filter, and dry the filter cake at 55 °C for 8 h to obtain 132.2 g of ferric pyrophosphate citrate.

[0025] Comparative Example 1 This comparative example provides a preparation method of ferric pyrophosphate citrate, which is different from Example 1 in that: there is no ferrous sulfate in the raw materials, and it specifically includes the following contents: Step 1: Dissolve 50.9 g of ferric sulfate nonahydrate in 150 g of deionized water, stir at 38 °C for 8 h to obtain a ferric sulfate solution; add 58.8 g of sodium citrate dihydrate to the ferric sulfate solution, and mix evenly to obtain a first reaction solution; Step 2: Add 44.6 g of sodium pyrophosphate to the first reaction solution, stir for 2 h, dissolve, filter, and obtain a second reaction solution; Step 3: Add the second reaction solution to 150 g of anhydrous methanol, perform crystallization at 35 °C for 2 h, filter, and dry the filter cake at 50 °C for 8 h to obtain 132.2 g of ferric pyrophosphate citrate.

[0026] To further demonstrate the technical effects of the present invention, the sodium citrate pyrophosphate obtained in Examples 1-6 and Comparative Example 1 was tested for its content. Among them, the sodium content was tested according to the atomic absorption spectrophotometry method in General Principles 0406, Volume IV of Ch.P. 2015; the ferric iron content was tested by volumetric method; the citrate content was tested according to the ion chromatography method in General Principles 0513, Volume IV of Ch.P. 2015; the sulfate content was tested according to the ion chromatography method in General Principles 0513, Volume IV of Ch.P. 2015; the pyrophosphate content was tested according to the ion chromatography method in General Principles 0513, Volume IV of Ch.P. 2015; the ferrous salt content was tested according to the potentiometric titration method and the water-stop titration method in General Principles 0701, Volume IV of Ch.P. 2015; the phosphoric acid content was tested according to the ion chromatography method in General Principles 0513, Volume IV of Ch.P. 2015. The results are shown in Table 1.

[0027] Table 1 Test results of component contents of sodium citrate pyrophosphate obtained in each example and comparative example

[0028] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, or improvements made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. A preparation method of ferric pyrophosphate citrate, characterized in that: It includes the following steps: Step 1: Dissolve ferrous sulfate in deionized water to obtain a ferrous sulfate solution; add ferric sulfate to the ferrous sulfate solution, and stir at 35 - 45 °C for 3 - 5 h to obtain a ferric sulfate solution; add sodium citrate to the ferric sulfate solution and mix evenly to obtain a first reaction solution; Step 2: Add sodium pyrophosphate to the first reaction solution to obtain a second reaction solution; Step 3: Add the second reaction solution to a crystallization solvent for crystallization to obtain ferric pyrophosphate citrate; Among them, the mass ratio of ferrous sulfate to ferric sulfate is 3:97 - 0.5:99.5; the concentration of the ferric sulfate solution is 0.1 mol / L - 0.4 mol / L.

2. The preparation method of ferric pyrophosphate citrate according to claim 1, characterized in that: The mass ratio of ferrous sulfate to ferric sulfate is 2:98 - 0.5:99.

5.

3. The preparation method of ferric pyrophosphate citrate according to claim 1, wherein: The molar ratio of ferric sulfate to sodium citrate is 1:1.5 - 1:2.

5.

4. The preparation method of ferric pyrophosphate citrate according to claim 1, wherein: The molar ratio of ferric sulfate to sodium pyrophosphate is 1:1 - 1:1.

2.

5. The preparation method of ferric pyrophosphate citrate according to claim 1, characterized in that: The mass ratio of ferric sulfate to the crystallization solvent is 1:2.5 - 1:3.

5.

6. The preparation method of ferric pyrophosphate citrate according to claim 1, characterized in that: The crystallization solvent is anhydrous methanol.

7. The preparation method of ferric pyrophosphate citrate according to claim 1, wherein: The temperature of the crystallization is 20 °C - 40 °C, and the time of the crystallization is 1 h - 3 h.

8. The preparation method of ferric pyrophosphate citrate according to claim 1, characterized in that: The temperature of the drying is 45 °C - 55 °C, and the time of the drying is 7 h - 10 h.

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