CN112457350A - Ferric pyrophosphate citrate complex and preparation method thereof - Google Patents
Ferric pyrophosphate citrate complex and preparation method thereof Download PDFInfo
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- CN112457350A CN112457350A CN202011373898.9A CN202011373898A CN112457350A CN 112457350 A CN112457350 A CN 112457350A CN 202011373898 A CN202011373898 A CN 202011373898A CN 112457350 A CN112457350 A CN 112457350A
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- ferric
- pyrophosphate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
- C07F15/02—Iron compounds
- C07F15/025—Iron compounds without a metal-carbon linkage
Abstract
The invention discloses a ferric pyrophosphate citrate complex and a preparation method thereof, the ferric sulfate, sodium citrate and sodium pyrophosphate are sequentially added into an acid regulator, and then the ferric pyrophosphate citrate complex is prepared by heating and stirring.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a ferric pyrophosphate citrate complex and a preparation method thereof.
Background
Hemodialysis is a kidney replacement therapy mode for patients with acute and chronic renal failure, and about 100 million patients with end-stage renal disease (ESRD) exist at present in the whole country. Renal failure necessitates replacement therapy and requires life-long maintenance therapy.
Hemoglobin fluctuation often occurs in hemodialysis patients during dialysis, and the hemoglobin fluctuation can obviously increase the patient hospitalization rate, the incidence rate of cardiovascular events, sudden death and other complications. At present, the measures generally adopted clinically are to supplement iron agents in advance or in the later period.
FDA approved Triferic (ferric pyrophosphate citrate solution) for commercial sale at 1 month 2015. Triferic is used as an iron substitute to help maintain hemoglobin in dialysis-dependent chronic kidney disease patients. The iron agent is added into bicarbonate dialysate for use, so that adverse reaction of a patient due to iron deficiency in the dialysis process is avoided, and the iron content of blood of the patient is always in a normal range.
The structural formula of the ferric pyrophosphate citrate complex is as follows:
patent CN 106977552 discloses a preparation method of ferric pyrophosphate citrate mixed complex: preparing an aqueous solution containing ferric iron cations, slowly dropwise adding the aqueous solution into the prepared mixed aqueous solution of pyrophosphate anions and citric acid anions, stirring and reacting for 1-2 hours after dropwise adding to obtain a dark green solution, filtering out insoluble substances, dropwise adding the filtrate into a crystallization solvent, continuously stirring for 1-2 hours after dropwise adding to obtain a light green solid, and drying to obtain the citric acid ferric pyrophosphate mixed complex. The preparation method adopts ferric sulfate aqueous solution to carry out dropwise reaction, ferric sulfate is slowly dissolved in cold water, the dissolution time is long, and in the process, the dropwise reaction method is adopted to carry out reaction, and the reaction time is also prolonged.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a preparation method of a ferric citrate pyrophosphate complex and the ferric citrate pyrophosphate complex prepared by the preparation method, so that the ferric citrate pyrophosphate complex can be quickly prepared.
The invention is realized by the following steps:
in a first aspect, the invention provides a preparation method of ferric citrate pyrophosphate complex, which comprises the steps of sequentially adding ferric sulfate, sodium citrate and sodium pyrophosphate into an acid regulator aqueous solution, and precipitating a reaction solution obtained by reaction through an organic solvent to obtain ferric citrate pyrophosphate complex solid.
Preferably, the reaction is carried out at a temperature of 25-80 ℃.
Preferably, the reaction is carried out at 55-65 ℃.
The ferric sulfate is dissolved quickly at the temperature of 55-65 ℃, the reaction speed is improved, and meanwhile, the sodium pyrophosphate is not easy to degrade under the condition.
In an alternative embodiment, the preparation method further comprises a purification step of ferric pyrophosphate citrate complex.
Preferably, the method of the purification step of the ferric citrate pyrophosphate complex comprises recrystallization of the ferric citrate pyrophosphate complex.
Preferably, the recrystallization method comprises the steps of re-dissolving the solid ferric citrate pyrophosphate complex, adding an organic solvent to re-precipitate the ferric citrate pyrophosphate complex, and drying to obtain the purified ferric citrate pyrophosphate complex, so that impurities in the ferric citrate pyrophosphate complex are removed.
In an alternative embodiment, the ferric pyrophosphate citrate complex is reprecipitated by adding an organic solvent at a pH of 3.0 to 7.0, including but not limited to 3.0, 4.0, 5.0, 6.0 or 7.0.
Preferably, the pH is 5.0. The ferric pyrophosphate citrate complex obtained when the pH value is 5.0 has higher stability.
Preferably, the pH is adjusted by the addition of a pH adjuster.
In alternative embodiments, the pH adjusting agent comprises one or a combination of two or more of sodium carbonate, sodium bicarbonate, or sodium hydroxide.
In an alternative embodiment, the drying method comprises drying under reduced pressure or forced air drying.
In alternative embodiments, the drying temperature is from 30 ℃ to 60 ℃, including but not limited to 30 ℃, 40 ℃, 50 ℃ or 60 ℃, preferably 45 ℃.
In an alternative embodiment, the organic solvent comprises one or a combination of two or more of methanol, ethanol, acetone, acetonitrile or dichloromethane, and the organic solvent is immiscible with ferric pyrophosphate citrate.
In alternative embodiments, the acidity regulator comprises one or a combination of more than two of citric acid, sulfuric acid, or pyrophosphoric acid.
In an optional embodiment, the mass ratio of the added substances of ferric sulfate and sodium citrate is 1: 1.5-2.5, the mass ratio of the added substances of ferric sulfate and sodium pyrophosphate is 1: 1-2, the mass ratio of ferric sulfate and an acid regulator substance is 1: 0.2-1, the mass volume ratio of ferric sulfate and water is 1g: 3-5 ml, and the content of each ion in the product obtained by adopting the mixture ratio is within the requirement range of the limit of a complex compound.
In a second aspect, the embodiment of the present invention provides an iron pyrophosphate citrate complex obtained by the preparation method described in the foregoing embodiment.
The invention has the following beneficial effects:
compared with the prior art, the method has the advantages that the ferric sulfate is dissolved more quickly by adjusting the adding sequence of the ferric sulfate, the sodium citrate and the sodium pyrophosphate, and the sodium citrate and the sodium pyrophosphate can be ensured to be in an acidic condition, so that the ferric pyrophosphate citrate complex obtained by the reaction can not be degraded. Then reacting to obtain a ferric citrate pyrophosphate complex, and precipitating by using a one-step organic solvent to obtain a ferric citrate pyrophosphate complex solid, wherein the whole reaction process is simple to operate and short in time consumption; meanwhile, the acidic regulator is added, so that the hydrolysis of ferric sulfate to form ferric hydroxide can be inhibited, the degradation of citric acid ions can be inhibited, the dissolving speed of ferric sulfate is obviously accelerated, and the reaction time is further shortened.
Detailed Description
In order to make the objects, 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. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
Adding 0.6L of water into a reaction bottle I, adding 17g of sulfuric acid, adding 150g of ferric sulfate hydrate, stirring to dissolve, adding 172g of sodium citrate, stirring to dissolve, adding 195g of sodium pyrophosphate, and stirring at 60 ℃ for 30min to obtain a reaction solution containing ferric pyrophosphate citrate complex.
Adding 2.25L of absolute ethyl alcohol into the reaction bottle II, then adding the reaction solution containing the citric acid ferric pyrophosphate complex obtained in the reaction bottle I at 25 ℃, stirring simultaneously, and filtering after 1 hour to obtain a yellow-green solid.
Example 2
Adding 0.6L of water into a reaction bottle I, adding 11g of sulfuric acid, adding 150g of ferric sulfate hydrate, stirring to dissolve, adding 154.8g of sodium citrate, stirring to dissolve, adding 169g of sodium pyrophosphate, and stirring at 60 ℃ for 30min to obtain a reaction solution containing ferric pyrophosphate citrate complex.
Adding 2.25L of absolute ethyl alcohol into the reaction bottle II, then adding the reaction solution containing the citric acid ferric pyrophosphate complex obtained in the reaction bottle I at the temperature of 20 ℃, stirring simultaneously, and filtering after 1 hour to obtain a yellow-green solid.
Example 3
Adding 0.6L of water into a reaction bottle I, adding 17g of sulfuric acid, adding 150g of ferric sulfate hydrate, stirring for dissolving, adding 172g of sodium citrate, stirring for dissolving, adding 195g of sodium pyrophosphate, and stirring at 55-65 ℃ for 30min to obtain a reaction solution containing the ferric pyrophosphate citrate complex.
Adding 2L of methanol into the reaction bottle II, adding the reaction solution containing the ferric pyrophosphate citrate complex obtained in the reaction bottle I at 20 ℃, stirring simultaneously, and filtering after 30min to obtain a yellow-green solid.
Example 4
Adding 0.6L of water into a reaction bottle I, adding 17g of sulfuric acid, adding 150g of ferric sulfate hydrate, stirring for dissolving, adding 210g of sodium citrate, stirring for dissolving, adding 260g of sodium pyrophosphate, and stirring at 55-65 ℃ for 30min to obtain a reaction solution containing the ferric pyrophosphate citrate complex.
And adding 2.25L of absolute ethyl alcohol into the reaction bottle II, adding the reaction solution containing the ferric pyrophosphate citrate complex obtained in the reaction bottle I at the temperature of 20-30 ℃, stirring simultaneously, and filtering after 30min to obtain a yellow-green solid.
Example 5
The pale green solid obtained in example 1 was added to 0.75L of water, and after dissolution, the pH was adjusted to 5.0 with sodium hydrogencarbonate to obtain a reconstituted solution.
And adding the redissolved solution into 3L of absolute ethyl alcohol, stirring while adding to separate out a solid, continuously stirring for 1 hour, and filtering to obtain a light green solid. The obtained solid was dried at 45 ℃ under reduced pressure for 20 hours to obtain 390g of a product with a yield of 97.0%.
Example 6
The pale green solid obtained in example 2 was added to 0.75L of water, and after dissolution, the pH was adjusted to 4.5 with sodium hydrogencarbonate to obtain a reconstituted solution.
And adding the redissolved solution into 3L of absolute ethyl alcohol, stirring while adding to separate out a solid, continuously stirring for 1 hour, and filtering to obtain a light green solid. The solid obtained was dried at 50 ℃ under reduced pressure for 20 hours to give 385g of product with a yield of 95.8%.
Example 7
The pale green solid obtained in example 3 was added to 0.75L of water, and after dissolution, the pH was adjusted to 5.0 with sodium hydrogencarbonate to obtain a reconstituted solution.
And adding the redissolved solution into 2.5L of methanol while stirring to separate out a solid, continuously stirring for 0.5 hour, and filtering to obtain a light green solid. The solid obtained was dried at 60 ℃ under reduced pressure for 14 hours to give 375g of product in 93.3% yield.
Example 8
The pale green solid obtained in example 4 was added to 0.7L of water, and after dissolution, the pH was adjusted to 6.0 with sodium carbonate to obtain a reconstituted solution.
And adding 3L of the redissolved solution into absolute ethyl alcohol while stirring to separate out a solid, continuously stirring for 0.5 hour, and filtering to obtain a light green solid. The resulting solid was dried at 45 ℃ under reduced pressure for 20 hours to give 382g of product with a yield of 95.0%.
Comparative example 1
25.23g of ferric sulfate hydrate is added into a reaction bottle I, 126.2g of purified water is added, and the mixture is stirred for 12 hours at 25 ℃, so that the solid is completely dissolved.
Adding 29.41g of sodium citrate into a reaction bottle II, adding 88.3g of purified water, stirring for 1 hour at 25 ℃, and completely dissolving; 44.61g of sodium pyrophosphate was added to the reaction flask III, and 669.2g of purified water was added thereto, and the mixture was stirred at 25 ℃ for 1 hour to be completely dissolved. The completely dissolved sodium pyrophosphate aqueous solution is slowly added into the sodium citrate aqueous solution, and stirred for 2 hours at 25 ℃.
And dropwise adding the prepared ferric sulfate solution into the mixed solution under stirring, wherein the dropwise adding is completed within 0.5 hour, and the stirring reaction is performed for 2 hours at 25 ℃ after the dropwise adding is completed to obtain a dark green solution, and filtering.
Adding 2.65L of methanol into the reaction bottle IV, dropwise adding the obtained filtrate under stirring, completing dropwise adding for 10 minutes to generate light green precipitate, continuing stirring for 1 hour, and filtering. The obtained solid was dried under reduced pressure at 40 ℃ for 16 hours to obtain 65.58g of a product.
Comparative example 2
11.2g sodium citrate and 8.5g sodium pyrophosphate were added to the reaction flask. Preparing a ferric sulfate solution with the concentration of 0.2 g/ml. 25ml of ferric sulfate solution is added into the reaction flask, stirred and heated to 80-85 ℃. All the substances were dissolved. Stopping heating, stirring and adding 10g of ferric sulfate, and cooling to room temperature. A dark green clear solution was obtained. 70ml of methanol was added with stirring to form a pale green precipitate, which was stirred for 5 minutes and filtered to give a pale green solid.
The obtained light yellow green solid is dried in a vacuum drying oven at 70-75 ℃ for 24 hours to obtain 18.5g of a product.
Comparative example 3
Adding 0.6L of water into a reaction bottle I, adding 17g of sulfuric acid, adding 172g of sodium citrate, stirring to dissolve, adding 150g of ferric sulfate hydrate, stirring to dissolve, adding 195g of sodium pyrophosphate, and stirring at 60 ℃ for 30min to obtain a reaction solution containing the ferric pyrophosphate citrate complex.
Adding 2.25L of absolute ethyl alcohol into the reaction bottle II, then adding the reaction solution containing the citric acid ferric pyrophosphate complex obtained in the reaction bottle I at 25 ℃, stirring simultaneously, and filtering after 1 hour to obtain a light green solid.
Comparative example 4
The pale green solid obtained in comparative example 3 was added to 0.75L of water, and after dissolution, the pH was adjusted to 5.0 with sodium hydrogencarbonate to obtain a redissolved solution.
And adding the redissolved solution into 3L of absolute ethyl alcohol, stirring while adding to separate out a solid, continuously stirring for 1 hour, and filtering to obtain a light green solid. The solid obtained was dried at 45 ℃ under reduced pressure for 20 hours to obtain 362g of a product with a yield of 90.0%.
Examples of the experiments
The iron, sulfate, citrate, pyrophosphate and phosphate in the obtained ferric pyrophosphate citrate complex were detected by titration and ion chromatography in examples 1 to 4, respectively, and the detection results are shown in table 1. The results of the tests of example 1 and comparative examples 1 to 3 are shown in Table 2.
TABLE 1 content table of each component in ferric pyrophosphate citrate complexes obtained in examples 1-4
It can be seen from table 1 that the ion compositions of the products obtained in examples 1 to 4 of the present invention are within the range of the limit requirement of the complex, and the obtained products are proved to be the complex.
TABLE 2 content table of each component in ferric pyrophosphate citrate complex obtained in example 1 and comparative examples 1 to 3
As can be seen from Table 2, comparative example 3 employs a preparation method similar to that of example 1 of the present application, except that the order of addition of the components is changed, and the citrate content in the obtained product does not meet the limit requirement, so that the stability of the obtained complex product is poor.
The yields of the products obtained by comparing the above examples 5 to 8 with comparative examples 1, 2 and 4 and the time taken for the reaction are shown in Table 3.
TABLE 3 comparison of the yields and times of reaction of the products obtained in examples 5 to 8 and comparative examples 1, 2 and 4
| Detecting items | Yield (%) | Reaction time (h) |
| Example 5 | 97 | About 22 |
| Example 6 | 95.8 | About 22 |
| Example 7 | 93.3 | About 16 |
| Example 8 | 95.0 | About 22 |
| Comparative example 1 | 92.1 | About 32 |
| Comparative example 2 | 90.1 | About 30 |
| Comparative example 4 | 90.0 | About 22 |
As can be seen from Table 3, the products obtained in examples 5 to 8 of the present invention are higher in yield and less time consuming than those obtained in comparative examples 1 and 2, and the product obtained in comparative example 4 by post-treating the product obtained in comparative example 3 by the treatment method of example 5 of the present application is lower in yield than that of example 5.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A preparation method of ferric citrate pyrophosphate complex is characterized by comprising the steps of sequentially adding ferric sulfate, sodium citrate and sodium pyrophosphate into an aqueous solution of an acid regulator, and precipitating a reaction solution obtained by reaction through an organic solvent to obtain ferric citrate pyrophosphate complex solid;
preferably, the reaction is carried out at a temperature of 25-80 ℃;
preferably, the reaction is carried out at 55-65 ℃.
2. The process according to claim 1, further comprising a step of purifying the ferric pyrophosphate citrate complex;
preferably, the method of the purification step of the ferric citrate pyrophosphate complex comprises recrystallizing the ferric citrate pyrophosphate complex;
preferably, the recrystallization method comprises the steps of re-dissolving the ferric citrate pyrophosphate complex solid, adding an organic solvent to re-precipitate the ferric citrate pyrophosphate complex, and drying to obtain the purified ferric citrate pyrophosphate complex.
3. The preparation method according to claim 2, wherein under the condition that the pH is 3.0-7.0, adding an organic solvent to re-precipitate the ferric pyrophosphate citrate complex;
preferably, the pH is 5.0;
preferably, the pH is adjusted by the addition of a pH adjuster.
4. The method according to claim 3, wherein the pH adjuster comprises one or a combination of two or more of sodium carbonate, sodium bicarbonate, and sodium hydroxide.
5. The method according to any one of claims 2 to 4, wherein the drying method comprises drying under reduced pressure or drying by air blowing.
6. The method according to claim 5, wherein the drying temperature is 30 ℃ to 60 ℃, preferably 45 ℃.
7. The method according to any one of claims 1 to 3, wherein the organic solvent comprises one or a combination of two or more of methanol, ethanol, acetone, acetonitrile, and dichloromethane.
8. The method of claim 1, wherein the acidity regulator comprises one or more of citric acid, sulfuric acid, and pyrophosphoric acid.
9. The preparation method according to claim 1 or 8, wherein the mass ratio of the input substances of ferric sulfate and sodium citrate is 1: 1.5-2.5, the mass ratio of the input substances of ferric sulfate and sodium pyrophosphate is 1: 1-2, the mass ratio of ferric sulfate and acidic regulator substance is 1: 0.2-1, and the mass volume ratio of ferric sulfate and water is 1g: 3-5 ml.
10. The ferric pyrophosphate citrate complex obtained by the preparation method of any one of claims 1 to 9.
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| DE69418346D1 (en) * | 1993-12-30 | 1999-06-10 | Kemira Oy | METHOD FOR PRODUCING COMPOUNDS BASED ON IRON (III) SULFATE AND HYDROXIDE |
| US20170095509A1 (en) * | 2015-10-05 | 2017-04-06 | Mahendra R. Patel | Preparation of Pharmaceutical Dosage Forms Containing Iron (III) Salts |
| CN106619494A (en) * | 2016-10-10 | 2017-05-10 | 泰州海达医药科技有限公司 | Citric acid ferric pyrophosphate solution and preparation method thereof |
| CN106977552A (en) * | 2016-01-19 | 2017-07-25 | 山东诚创医药技术开发有限公司 | The preparation method of citric acid ferric pyrophosphate mixed air EDM |
| CN108883085A (en) * | 2016-01-06 | 2018-11-23 | 罗克韦尔医疗公司 | With the composition therapy of iron compound and citrate compound |
| CN111116350A (en) * | 2019-12-28 | 2020-05-08 | 湖南九典制药股份有限公司 | Preparation method of potassium sodium hydrogen citrate |
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2020
- 2020-11-30 CN CN202011373898.9A patent/CN112457350A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69418346D1 (en) * | 1993-12-30 | 1999-06-10 | Kemira Oy | METHOD FOR PRODUCING COMPOUNDS BASED ON IRON (III) SULFATE AND HYDROXIDE |
| US20170095509A1 (en) * | 2015-10-05 | 2017-04-06 | Mahendra R. Patel | Preparation of Pharmaceutical Dosage Forms Containing Iron (III) Salts |
| CN108883085A (en) * | 2016-01-06 | 2018-11-23 | 罗克韦尔医疗公司 | With the composition therapy of iron compound and citrate compound |
| CN106977552A (en) * | 2016-01-19 | 2017-07-25 | 山东诚创医药技术开发有限公司 | The preparation method of citric acid ferric pyrophosphate mixed air EDM |
| CN106619494A (en) * | 2016-10-10 | 2017-05-10 | 泰州海达医药科技有限公司 | Citric acid ferric pyrophosphate solution and preparation method thereof |
| CN111116350A (en) * | 2019-12-28 | 2020-05-08 | 湖南九典制药股份有限公司 | Preparation method of potassium sodium hydrogen citrate |
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