AN IMPROVED PROCESS FOR THE PREPARATION OF , FERRIC CITRATE
TECHNICAL FIELD:
This invention relates to improved process for preparation of ferric organic compounds, such as Ferric citrate.
BACKGROUND ART:
Ferric iron containing compounds are useful in the treatment of a number of disorders, including, but not limited to, hyperphosphatemia and metabolic acidosis.
Ferric iron containing compounds existing in the art are for example Ferric chloride, Ferric oxide, Ferric fluoride, and Ferric citrate.
Elevated amounts of phosphate in the blood can be removed by administering compounds such as Ferric citrate. Once in solution, the ferric iron binds phosphate, and the ferric phosphate compounds precipitate in the gastrointestinal tract, resulting in effective removal of dietary phosphate from the body. It is also believed that the absorbed citrate from of Ferric citrate is converted to bicarbonate which corrects metabolic acidosis, a condition common in renal failure patients.
Ferric citrate has the following structure, and can be referred to as FCT.


The novel form of Ferric citrate has the formula Ce^C^Fe and has novel physical properties as determined by dissolution rates, and has a molecular weight of 244.94 g/mole. Ferric citrate is approved in 2014 in USA, and the NDA applicant is Keryx Pharmaceuticals.
Pharmaceutical grade Ferric citrate is suitable for treating hyperphosphatemia, or other disorders characterized by high serum phosphate levels. Specifically, for treating subjects or patients with various renal diseases; e.g., End Stage Renal Diseases (ESRD), Chronic Kidney Disease (CKD) or other related kidney diseases, or subjects and patients who are on dialysis but not limited to hemodialysis.
Ferric citrate is characterized as a light brown to beige powder, odorless and slightly ferruginous tasting. According to the Merck Index, Ferric citrate is slowly but completely soluble in cold water and readily soluble in hot water but diminishes in solubility with age.
The following patents and patent publications describe processes for preparation of Ferric Citrate.
US 7767851 describes preparation of Ferric Citrate by adding alkaline metal hydroxide solution to a ferric chloride solution, isolating ferric hydroxide precipitate, followed by adding citric acid, with subsequent heating, addition of an organic solvent, and precipitating Ferric Citrate.
US 6903235 relates to process for the preparation of Ferric Citrate which involves mixing solid citric acid with solid ferric salt to form a mixture followed by addition of alcohol to the mixture, and further filtration of the mixture to obtain solid ferric citrate.
US 9624155 discloses a method for preparation of Ferric citrate, wherein ferric chloride was reacted with sodium hydroxide in an aqueous medium for 2 hrs or less at a temperature of 0 -10°c, contacting Iron containing precipitate with citric acid and generating aqueous solution of Iron (III) citrate, which was precipitated using an organic solvent.
WO 2015/110968 describes process for preparation of Ferric citrate which involves combining citrate ion source with Ferric ion source in water followed by adding alcohol, and precipitating Ferric citrate.

WO 2017/021921 relates a process for preparation of Ferric Citrate by combining a Ferric source with citrate source and base in water, and adding an organic solvent to the above mixture to yield Ferric citrate precipitate followed by drying.
WO2016162888 relatesno process" for preparation of ferric"citrate which involves adding a
ferric salt to alkali metal carbonate, followed by addition of a coagulating agent to obtain ferric oxohydride mass which is then added citric acid and was heated to obtain a solution followed by addition of an organic solvent to obtain Ferric citrate.
WO 2016098131 discusses process for preparation of Ferric citrate by adding alkali metal carbonate to an aqueous solution of ferric chloride and isolating solid ferric hydroxide at pH ranging from 6.8 to 8.5, followed by addition of ferric hydroxide to an aqueous solution of citric acid monohydrate and heating to 80-120°c, further precipitating ferric citrate.
US 2,081,547 which involves preparation of Ferric citrate by dissolving Ferric hydroxide in citric acid to form the ferric citric acid/Ferric citrate. Wherein ferric hydroxide is prepared by addition of ammonium hydroxide/sodium bicarbonate to ferric chloride.
Most of the above reported procedures are either tedious and not suitable for industrial scale production.
Accordingly, there exists a need for improved/technologically advanced/economically feasible/scalable process of Ferric organic compounds or Ferric citrate for human use, which meets all the required specification as a drug.
SUMMARY OF THE INVENTION:
The present invention in one aspect provides a method for preparing Ferric Citrate. The method comprising the steps of:
a) Treating a ferric ion source with ammonium hydroxide in an aqueous medium for duration of one and half hour or less at a liquid temperature of 25 to 35°c at a pH in a range between 7.2-7.8.

b) Treating the resulting iron-containing precipitate with citric acid in an aqueous medium and generating an aqueous solution of ferric citrate via heating at a temperature of 75-85°c for a time period of two hours or less;
c).Precipitating ferric citrate comprising bringing the aqueous solution of ferric citrate into contact with an organic solvent, and drying at 25-35°C for 8 to 10 hours and further at 40-45°C for 10-12hours to yield ferric citrate.
DETAILED DESCRIPTION:
The present invention relates to a method for producing ferric citrate. The method of the present invention comprises a step of forming an iron-containing precipitate, a step of generating an aqueous solution of ferric citrate, and a step of precipitating ferric citrate. These steps are described below.
a) Step of Forming Iron-Containing Precipitate:
This step is intended to form an iron-containing precipitate by bringing ferric ion source into contact with ammonium hydroxide in an aqueous medium.
Ferric ion source is chosen from ferric chloride, ferric sulfate, and ferric nitrate. Preferably, ferric chloride is used as the ferric ion source in reaction with ammonium hydroxide.
Ferric chloride used in this step may be in the form of an anhydrate or hydrate thereof. Alternatively, it may be in the form of an aqueous solution thereof. Ferric chloride of any form can be used in the method of the present invention. Preferably the source of ferric ion is ferric chloride hexahydrate.
Prior to contacting the ferric ion source with ammonium hydroxide, the ferric ion source is purified by way of washing/filtration with organic solvent.
Then the reaction mass was diluted with water. The pH was adjusted to 7.2 to 7.8 with ammonium hydroxide solution in water at 25-30°C. The obtained solid precipitate was stirred for l-l'/i hours at 25-35°C, filtered, washed with water.
b) Step of forming ferric citrate:

The above material was added to stirred solution of citrate ion source in water, for 15-20 min at 25-35°C. After addition, the reaction mass was slowly heated to 75-85°C and maintained for 30 min, then citrate ion source solution was slowly added till the time reaction mass became a clear solution. Then the reaction mixture was maintained at 75-85°C for l'/2-2hours. After maintenance, the reaction mass was filtered and washed with water. The solution was cooled to 25-35°C and was filtered, followed by addition of organic solvent and the reaction mass was maintained at 25-35°C for 25-30 min. The obtained solid precipitate was stirred for 1-1'/i hours at 25-35°C, filtered, and suck dried.
The above material was stirred with organic solvent at 25-35°C for 3-4 hours. The solid precipitate was filtered, and suck dried. The material was dried at 25-35°C for 8-10 hours and further at 40-45°C for 10-12 hours till ferric content is between 20.6-22.1% to afford 1,2,3-Propanetricarboxylicacid, 2-hydroxy-iron salt, ferric citrate as a light brown to beige amorphous powder.
The citrate ion source is citric acid, preferably the citrate ion source is anhydrous citric acid.
According to the above embodiments, the organic solvent is selected from ethanol, methanol, butanol, acetone, isopropyl alcohol or tetrahydrofuran, preferably the organic solvent is acetone.
The following examples illustrate various aspects of the present invention. They are not to be construed to limit the claims in any manner whatsoever.
Examples:
To a stirred solution of ferric chloride hexahydrate (200.0 g, 1.0) in Acetone (600.0 mL, 3.0 volumes), then filtered through Hyflo bed and washed with (100.0 mL, 0.5 volume). The combined filtrate charge back into the RBF, then the reaction mass was diluted with DM water (1200.0 mL, 6.0 volumes). The pH was adjusted to 7.2 to 7.8 with 50% ammonium hydroxide (210.0 g) solution in water (210.0 mL of DM water) at 25-30°C. The obtained solid precipitate was stirred for l-l'/z hours at 25-35°C, filtered, washed with DM water (400.0 mL, 2.0 volumes), sucked dry and unloaded the wet material.
To a stirred solution of anhydrous citric acid (212.0 g, 1.50 eq) in DM water (1200.0 mL, 6.0 volumes), the above wet material was added to the citric acid solution for 15-20 min

at 25-35°C . After addition, the reaction mass was slowly heated to 75-85°C and maintained for 30 min. then slowly add anhydrous citric acid solution (36.0 g, 0.25 eq in 40 mL of DM water) at the time reaction mass became a clear solution. Then the reaction mixture was maintained at 75-85°C for l1/>2hours. After maintenance, the reaction mass was filtered through hyflo bed and washed with DM water (100 mL, 0.5 volume). The combined filtrate was cooled to 25-35cC slowly filtered acetone (4000.0 mL) was added to the reaction mass at 25-35°C for 25-30 min. The obtained solid precipitate was stirred for 1-1 xh hours at 25-35°C, filtered, washed with filtered acetone (200.0 mL, 1.0 volume), sucked dry and unloaded the wet material.
The above wet material was stirred with filtered acetone (600.0 mL, 3.0 volumes) at 25-35°C for 3-4 hours.The solid precipitate was filtered, washed with filtered acetone (100.0 mL, 1.0 volume), sucked dry and unloaded the wet material. The wet material was dried at 25-35°C for 8.0-10.0 hours and further at 40-45for 10-12hours, till ferric contentis between20.6-22.1% to afford 1,2,3-Propanetricarboxylicacid, 2-hydroxy-iron salt, Iron(m) Citrate( 122.0 g, 0.61% w/w) as a light brown to beige amorphous powder.
Claims:
1. A method for producing ferric citrate comprising: a step of forming an iron-containing precipitate comprising bringing ferric ion source into contact with ammonium hydroxide in an aqueous medium for a duration of one and half hour or less at a liquid temperature of 25 to 35°c at a pH in a range between 7.2-7.8 to form an iron-containing precipitate; a step of generating an aqueous solution of ferric citrate comprising bringing citrate ion source into contact with the iron-containing precipitate in an aqueous medium and generating an aqueous solution of ferric citrate via heating at a temperature of 75-85°c for a time period of two hours or less; and a step of precipitating ferric citrate comprising bringing the aqueous solution of ferric citrate into contact with an organic solvent and drying at 25-35°C for 8 tolO hours and further at 40-45°C for 10-12 hours.
2. A method for producing ferric citrate comprising: a step of forming an iron-containing precipitate comprising bringing ferric chloride into contact with ammonium hydroxide in an aqueous medium for a duration of one and half hour or less at a liquid temperature of 25 to 35°c

to form an iron-containing precipitate; a step of generating an aqueous solution of ferric citrate comprising bringing citric acid into contact with the iron-containing precipitate in an aqueous medium and generating an aqueous solution of ferric citrate via heating at a temperature of 75-85°c for a time period of two hours or less; and a step of precipitating ferric citrate comprising bringing the aqueous solution of ferric citrate into contact with acetone and drying at 25-35°C for 8 tolO hours and further at 40-45°C for 10-12 hours.
3. A method for producing ferric citrate comprising: a step of forming an iron-containing precipitate comprising bringing ferric chloride into contact with ammonium hydroxide in an aqueous medium for a duration of one and half hour or less at a pH in a range between 7.2-7.8 to form an iron-containing precipitate; a step of generating an aqueous solution of ferric citrate comprising bringing citric acid into contact with the iron-containing precipitate in an aqueous medium and generating an aqueous solution of ferric citrate via heating at a temperature of 75-85°c for a time period of two hours or less; and a step of precipitating ferric citrate comprising bringing the aqueous solution of ferric citrate into contact with acetone and drying at 25-35°C for 8 to 10 hours and further at 40-45°C for 10-12 hours.
4. A method for producing ferric citrate comprising: a step of forming an iron-containing precipitate comprising bringing ferric chloride into contact with ammonium hydroxide in an aqueous medium for a duration of one and half hour or less to form an iron-containing precipitate; a step of generating an aqueous solution of ferric citrate comprising bringing citric acid into contact with the iron-containing precipitate in an aqueous medium and generating an aqueous solution of ferric citrate via heating at a temperature of 75-85°c for a time period of two hours or less; and a step of precipitating ferric citrate comprising bringing the aqueous solution of ferric citrate into contact with acetone and drying at 25-35°C for 8 tolO hours and further at 40-45°C for 10-12hours.
5. The process according to claim 1, wherein the organic solvent is selected from ethanol, methanol, butanol, acetone, isopropyl alcohol or tetrahydrofuran.
6. The process according to claim 5, wherein the organic solvent is acetone.

7. The process according to claim 1, wherein the ferric ion source is ferric chloride, ferric nitrate, ferric sulfate or a hydrated form thereof.
8. The process according to claim 7, wherein the ferric ion source is ferric chloride hexahydrate.
9. The process according to claim 1, wherein the citrate ion source is citric acid.
10. The process according to claim 9, wherein the citrate ion source is citric acid anhydrous.