A citric acid pyrophosphate iron complex and its preparation method

Abstract

This invention discloses a ferric citrate pyrophosphate complex and its preparation method. The method involves sequentially adding ferric sulfate, sodium citrate, and sodium pyrophosphate to an acidic regulator, followed by heating and stirring to obtain the ferric citrate pyrophosphate complex. The entire reaction process is simple to operate. The addition of the acidic regulator significantly accelerates the dissolution rate of ferric sulfate, resulting in a short reaction time. At the same time, the formation of iron hydroxide is avoided under acidic conditions.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to a citrate pyrophosphate iron complex and its preparation method. Background Technology

[0002] Hemodialysis is a renal replacement therapy for patients with acute and chronic renal failure. There are currently about 1 million patients with end-stage renal disease (ESRD) in China. Renal failure requires replacement therapy and lifelong maintenance therapy.

[0003] Hemodialysis patients often experience fluctuations in hemoglobin levels during dialysis, and these fluctuations can significantly increase hospitalization rates, the incidence of cardiovascular events, and complications such as sudden death. Currently, the common clinical approach is to administer iron supplements before or after dialysis.

[0004] In January 2015, the FDA approved Triferic (ferric citrate pyrophosphate solution) for commercial sale. Triferic is an iron alternative to help maintain hemoglobin levels in dialysis-dependent patients with chronic kidney disease. This iron supplement is added to bicarbonate dialysate to ensure that patients do not experience adverse reactions due to iron deficiency during dialysis, while also ensuring that the patient's blood iron levels remain within the normal range.

[0005] The structural formula of the ferric citric acid pyrophosphate complex is as follows:

[0006]

[0007] Patent CN 106977552 discloses a method for preparing a ferric citrate pyrophosphate complex: An aqueous solution containing ferric ions is prepared and slowly added dropwise to a prepared aqueous solution containing pyrophosphate and citrate anions. After the addition is complete, the mixture is stirred for 1-2 hours to obtain a dark green solution. Insoluble matter is filtered off, and the filtrate is added dropwise to a crystallization solvent. After the addition is complete, stirring continues for 1-2 hours to obtain a light green solid. The ferric citrate pyrophosphate complex is then dried. This preparation method uses an aqueous solution of ferric sulfate for the dropwise reaction. Ferric sulfate dissolves slowly in cold water, resulting in a long dissolution time. Furthermore, the dropwise addition method further increases the reaction time.

[0008] In view of this, the present invention is proposed. Summary of the Invention

[0009] The purpose of this invention is to provide a method for preparing ferric citrate pyrophosphate complex and the ferric citrate pyrophosphate complex obtained by the method, so as to rapidly prepare ferric citrate pyrophosphate complex.

[0010] This invention is implemented as follows:

[0011] In a first aspect, the present invention provides a method for preparing a ferric citrate pyrophosphate complex, the method comprising: sequentially adding ferric sulfate, sodium citrate and sodium pyrophosphate to an aqueous solution of an acidic regulator; and precipitating the reaction solution with an organic solvent to obtain a solid ferric citrate pyrophosphate complex.

[0012] Preferably, the reaction is carried out at a temperature of 25–80°C.

[0013] Preferably, the reaction is carried out at 55-65°C.

[0014] Ferric sulfate dissolves more quickly at 55-65℃, increasing the reaction rate, while sodium pyrophosphate is less prone to degradation under these conditions.

[0015] In an optional embodiment, the preparation method further includes a purification step of the ferric citric acid pyrophosphate complex.

[0016] Preferably, the purification step of the citrate pyrophosphate iron complex includes recrystallizing the citrate pyrophosphate iron complex.

[0017] Preferably, the recrystallization method includes redissolving the solid citrate ferric pyrophosphate complex, adding an organic solvent to cause the citrate ferric pyrophosphate complex to precipitate again, and then drying it to obtain a purified citrate ferric pyrophosphate complex, thereby removing impurities from the citrate ferric pyrophosphate complex.

[0018] In an optional embodiment, an organic solvent is added to cause the ferric pyrophosphate citrate complex to redefine under conditions of pH 3.0 to 7.0, wherein the pH value includes, but is not limited to, 3.0, 4.0, 5.0, 6.0 or 7.0.

[0019] Preferably, the pH is 5.0. The ferric citrate pyrophosphate complex obtained at pH 5.0 exhibits higher stability.

[0020] Preferably, the pH is adjusted by adding a pH adjuster.

[0021] In an optional embodiment, the pH adjuster includes one or more of sodium carbonate, sodium bicarbonate, or sodium hydroxide.

[0022] In an optional embodiment, the drying method includes depressurization drying or forced-air drying.

[0023] In an optional embodiment, the drying temperature is 30°C to 60°C, including but not limited to 30°C, 40°C, 50°C or 60°C, preferably 45°C.

[0024] In an optional embodiment, the organic solvent includes one or more of methanol, ethanol, acetone, acetonitrile, or dichloromethane, and the organic solvent is immiscible with ferric pyrophosphate citrate.

[0025] In an optional embodiment, the acidity regulator includes one or more of citric acid, sulfuric acid, or pyrophosphate.

[0026] In an optional embodiment, the molar ratio of ferric sulfate to sodium citrate is 1:1.5 to 2.5, the molar ratio of ferric sulfate to sodium pyrophosphate is 1:1 to 2, the molar ratio of ferric sulfate to acid regulator is 1:0.2 to 1, and the mass-volume ratio of ferric sulfate to water is 1g:3 to 5ml. The content of each ion in the product obtained by using the above ratios is within the limit requirements of the complex.

[0027] Secondly, embodiments of the present invention provide a citric acid pyrophosphate iron complex obtained by the preparation method described in the foregoing embodiments.

[0028] The present invention has the following beneficial effects:

[0029] Compared with existing technologies, this invention achieves faster dissolution of ferric sulfate by adjusting the order of addition of ferric sulfate, sodium citrate, and sodium pyrophosphate, while ensuring that sodium citrate and sodium pyrophosphate are in acidic conditions, thus preventing the degradation of the resulting ferric citrate-pyrophosphate complex. The resulting ferric citrate-pyrophosphate complex is then precipitated using an organic solvent to obtain a solid ferric citrate-pyrophosphate complex. The entire reaction process is simple and time-efficient. Furthermore, the addition of an acid regulator inhibits the hydrolysis of ferric sulfate to form ferric hydroxide and suppresses the degradation of citrate ions, significantly accelerating the dissolution rate of ferric sulfate and further shortening the reaction time. Detailed Implementation

[0030] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0031] The features and performance of the present invention will be further described in detail below with reference to embodiments.

[0032] Example 1

[0033] Add 0.6L of water, 17g of sulfuric acid, and 150g of ferric sulfate hydrate to reaction flask I. After stirring and dissolving, add 172g of sodium citrate and stir and dissolve. Then add 195g of sodium pyrophosphate and stir at 60℃ for 30min to obtain a reaction solution containing ferric pyrophosphate citrate complex.

[0034] Add 2.25 L of anhydrous ethanol to reaction flask II, and then add the reaction solution containing ferric pyrophosphate citrate obtained in reaction flask I at 25 °C. Stir at the same time, and filter after 1 hour to obtain a yellow-green solid.

[0035] Example 2

[0036] Add 0.6L of water, 11g of sulfuric acid, and 150g of ferric sulfate hydrate to reaction flask I. After stirring and dissolving, add 154.8g of sodium citrate and stir and dissolve. Then add 169g of sodium pyrophosphate and stir at 60℃ for 30min to obtain a reaction solution containing ferric pyrophosphate citrate complex.

[0037] Add 2.25 L of anhydrous ethanol to reaction flask II, and then add the reaction solution containing ferric pyrophosphate citrate obtained in reaction flask I at 20 °C. Stir at the same time, and filter after 1 hour to obtain a yellow-green solid.

[0038] Example 3

[0039] Add 0.6L of water, 17g of sulfuric acid, and 150g of ferric sulfate hydrate to reaction flask I. After stirring and dissolving, add 172g of sodium citrate and stir and dissolve. Then add 195g of sodium pyrophosphate. Stir at 55-65℃ for 30 minutes to obtain a reaction solution containing ferric pyrophosphate citrate complex.

[0040] 2 L of methanol was added to reaction flask II, and then the reaction solution containing ferric pyrophosphate citrate complex obtained in reaction flask I was added at 20 °C. The mixture was stirred and filtered after 30 min to obtain a yellow-green solid.

[0041] Example 4

[0042] Add 0.6L of water, 17g of sulfuric acid, and 150g of ferric sulfate hydrate to reaction flask I. After stirring and dissolving, add 210g of sodium citrate and stir and dissolve. Then add 260g of sodium pyrophosphate and stir at 55-65℃ for 30 minutes to obtain a reaction solution containing ferric pyrophosphate citrate complex.

[0043] Add 2.25 L of anhydrous ethanol to reaction flask II, and then add the reaction solution containing ferric pyrophosphate citrate obtained in reaction flask I at 20-30 °C. Stir at the same time, and filter after 30 min to obtain a yellow-green solid.

[0044] Example 5

[0045] The light green solid obtained in Example 1 was added to 0.75 L of water, dissolved, and the pH was adjusted to 5.0 with sodium bicarbonate to obtain a reconstituted solution.

[0046] The reconstituted solution was then added to 3 L of anhydrous ethanol while stirring. A solid precipitated out, and after stirring for another hour, the mixture was filtered to obtain a light green solid. The obtained solid was dried under reduced pressure at 45 °C for 20 hours to yield 390 g of product, with a yield of 97.0%.

[0047] Example 6

[0048] The light green solid obtained in Example 2 was added to 0.75 L of water, dissolved, and the pH was adjusted to 4.5 with sodium bicarbonate to obtain a reconstituted solution.

[0049] The reconstituted solution was then added to 3 L of anhydrous ethanol while stirring. A solid precipitated out, and after stirring for another hour, the mixture was filtered to obtain a light green solid. The obtained solid was dried under reduced pressure at 50 °C for 20 hours to yield 385 g of product, with a yield of 95.8%.

[0050] Example 7

[0051] The light green solid obtained in Example 3 was added to 0.75 L of water, dissolved, and the pH was adjusted to 5.0 with sodium bicarbonate to obtain a reconstituted solution.

[0052] The reconstituted solution was then added to 2.5 L of methanol while stirring. A solid precipitated out, and after stirring for another 0.5 hours, the mixture was filtered to obtain a light green solid. The obtained solid was dried under reduced pressure at 60 °C for 14 hours to obtain 375 g of product, with a yield of 93.3%.

[0053] Example 8

[0054] The light green solid obtained in Example 4 was added to 0.7 L of water, dissolved, and the pH was adjusted to 6.0 with sodium carbonate to obtain a reconstituted solution.

[0055] The reconstituted solution was then added to 3 L of anhydrous ethanol while stirring. A solid precipitated out, and after stirring for another 0.5 hours, the mixture was filtered to obtain a light green solid. The obtained solid was dried under reduced pressure at 45 °C for 20 hours to yield 382 g of product, with a yield of 95.0%.

[0056] Comparative Example 1

[0057] Add 25.23g of ferric sulfate hydrate to reaction flask I, add 126.2g of purified water, stir at 25℃ for 12 hours until the solid is completely dissolved.

[0058] Add 29.41 g of sodium citrate to reaction flask II, then add 88.3 g of purified water and stir at 25°C for 1 hour until completely dissolved. Add 44.61 g of sodium pyrophosphate to reaction flask III, then add 669.2 g of purified water and stir at 25°C for 1 hour until completely dissolved. Slowly add the completely dissolved sodium pyrophosphate solution to the sodium citrate solution and stir at 25°C for 2 hours.

[0059] The prepared ferric sulfate solution was added dropwise to the mixed solution with stirring. The addition was completed in 0.5 hours. After the addition was completed, the mixture was stirred at 25°C for 2 hours to obtain a dark green solution, which was then filtered.

[0060] 2.65 L of methanol was added to reaction flask IV, and the filtrate obtained above was added dropwise with stirring. The addition was completed over 10 minutes, resulting in a light green precipitate. After stirring for another hour, the mixture was filtered. The resulting solid was dried under reduced pressure at 40 °C for 16 hours to obtain 65.58 g of product.

[0061] Comparative Example 2

[0062] Add 11.2 g of sodium citrate and 8.5 g of sodium pyrophosphate to a reaction flask. Prepare a ferric sulfate solution with a concentration of 0.2 g / ml. Add 25 ml of the ferric sulfate solution to the reaction flask, stir, and heat to 80-85°C. All substances dissolve completely. Stop heating, stir, and add 10 g of ferric sulfate, then cool to room temperature. A dark green clear solution is obtained. Add 70 ml of methanol while stirring; a light green precipitate forms. Continue stirring for 5 minutes, filter, and obtain a light green solid.

[0063] The obtained light yellow-green solid was dried in a vacuum drying oven at 70-75℃ for 24 hours to obtain 18.5g of product.

[0064] Comparative Example 3

[0065] Add 0.6L of water, 17g of sulfuric acid, and 172g of sodium citrate to reaction flask I. After stirring and dissolving, add 150g of ferric sulfate hydrate and stir and dissolve. Then add 195g of sodium pyrophosphate and stir at 60℃ for 30min to obtain a reaction solution containing ferric citrate pyrophosphate complex.

[0066] Add 2.25 L of anhydrous ethanol to reaction flask II, and then add the reaction solution containing ferric pyrophosphate citrate obtained in reaction flask I at 25 °C. Stir at the same time, and filter after 1 hour to obtain a light green solid.

[0067] Comparative Example 4

[0068] The light green solid obtained in Comparative Example 3 was added to 0.75 L of water, dissolved, and the pH was adjusted to 5.0 with sodium bicarbonate to obtain a reconstituted solution.

[0069] The reconstituted solution was then added to 3 L of anhydrous ethanol while stirring. A solid precipitated out, and after stirring for another hour, the mixture was filtered to obtain a light green solid. The obtained solid was dried under reduced pressure at 45 °C for 20 hours to yield 362 g of product, with a yield of 90.0%.

[0070] Experimental Example

[0071] The iron, sulfate, citrate, pyrophosphate, and phosphate groups in the obtained ferric citrate pyrophosphate complexes of Examples 1-4 were determined by titration and ion chromatography, respectively. The results are shown in Table 1. The results of Example 1 and Comparative Examples 1-3 are shown in Table 2.

[0072] Table 1. Content of each component in the citric acid pyrophosphate iron complexes obtained in Examples 1-4.

[0073]

[0074] As can be seen from Table 1, the composition of each ion in the products obtained in Examples 1 to 4 of the present invention is within the limit range of complexes, proving that the obtained products are complexes.

[0075] Table 2. Content of each component in the citric acid pyrophosphate complex obtained in Example 1 and Comparative Examples 1-3.

[0076]

[0077]

[0078] As can be seen from Table 2, Comparative Example 3 adopted a preparation method similar to that of Example 1 of this application, except that the order of addition of the components was changed. The citrate content in the product obtained did not meet the limit requirements, and therefore the stability of the obtained complex product was poor.

[0079] The yields and reaction times of the products obtained from Examples 5-8 and Comparative Examples 1, 2 and 4 are shown in Table 3.

[0080] Table 3. Comparison of yields and reaction times of products obtained from Examples 5-8 and Comparative Examples 1, 2, and 4.

[0081] Example 5 97 Approximately 22 Example 6 95.8 Approximately 22 Example 7 93.3 Approximately 16 Example 8 95.0 Approximately 22 Comparative Example 1 92.1 Approximately 32 Comparative Example 2 90.1 Approximately 30 Comparative Example 4 90.0 Approximately 22

[0082] As can be seen from Table 3, the product yields obtained in Examples 5-8 of the present invention are relatively high, and the time required is shorter compared with Comparative Examples 1 and 2. Comparative Example 4 uses the processing method of Example 5 of the present application to post-process the product obtained in Comparative Example 3, and the product yield obtained is lower than that of Example 5.

[0083] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing a citric acid pyrophosphate iron complex, characterized in that, The steps are as follows: Add 0.6L of water, 17g of sulfuric acid, and 150g of ferric sulfate hydrate to reaction flask I. After stirring and dissolving, add 172g of sodium citrate. After stirring and dissolving, add 195g of sodium pyrophosphate. Stir at 60℃ for 30min to obtain a reaction solution containing ferric pyrophosphate citrate complex. Add 2.25 L of anhydrous ethanol to reaction flask II, and then add the reaction solution containing citric acid pyrophosphate iron complex obtained in reaction flask I at 25 °C. Stir at the same time, and filter after 1 hour to obtain a yellow-green solid. The obtained yellow-green solid was added to 0.75L of water, dissolved, and the pH was adjusted to 5.0 with sodium bicarbonate to obtain a reconstituted solution. The reconstituted solution was then added to 3L of anhydrous ethanol while stirring. A solid precipitated out. After stirring for another hour, the mixture was filtered to obtain a light green solid. The light green solid was dried under reduced pressure at 45°C for 20 hours to obtain ferric pyrophosphate complex.

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