Claims:1. A process for the preparation of Ferric carboxymaltose, comprising: reacting oxidized one or more maltodextrins with ferric oxyhydroxide wherein oxidation of one or more maltodextrins is carried out using bromine solution at alkaline pH to provide Ferric carboxymaltose.
2. The process as claimed in claim 1, one maltodextrin is present, the maltodextrin has a dextrose equivalent of between 16 and 24, and when a mixture of more than one maltodextrins are present, the dextrose equivalent of each individual maltodextrin is between 5 and 40, and the dextrose equivalent of the mixture is between 16 and 24.
3. The process as claimed in claim 1, oxidation of one or more maltodextrins is carried out in alkaline pH range about 8 to 12 and reaction temperature ranges from about 15°C to 100°C.
4. The process as claimed in claim 1, Ferric carboxymaltose complex having a weight average molecular weight of 130 kDa to 350 kDa.
5. The process as claimed in claim 1, iron content of the obtained Ferric carboxymaltose complex is 28 to 34% weight/weight.
6. The process as claimed in claim 1, chloride content in obtained Ferric carboxymaltose complex is not more than 1% weight/weight.
7. The process as claimed in claim 1, osmolarity of obtained Ferric carboxymaltose complex is not more than 400 mOsmol/L.
8. The process as claimed in claim 1, average core particle size of iron in Ferric carboxymaltose complex is 20-30 nm. , Description:Field of the invention:
The present invention relates to an improved for the preparation of water soluble iron (III) carbohydrate complex.
Background of the invention:
Ferric carboxymaltose (FCM) complex is a stable, non-dextran, water soluble iron (III) carbohydrate complex indicated for the treatment of iron deficiency anaemia (IDA). Ferric carboxymaltose is a colloidal iron (III) hydroxide in complex with oxidised maltodextrins, a carbohydrate polymer that releases iron.
US7612109 B2 discloses water soluble iron carbohydrate complex (ferric carboxymaltose complex) comprising reaction product of an aqueous solution of an iron (III) salt and an aqueous solution of the oxidation product at least one maltodextrin and aqueous hypochlorite solution at an alkaline pH.
US20120214986A1 discloses a process for the preparation of iron (iii) carboxymaltose complex by oxidizing one or more maltodextrins using an aqueous sodium hypochlorite solution further reacting with ferric hydroxide to produce iron (III) carboxymaltose complex.
IN3474/CHE/2013 discloses a process for the preparation of ferric carboxymaltose complex by reacting an aqueous solution of ferric (III) complex with aqueous solution of oxidised maltodextrin wherein the oxidation is carried out using a non-hypohalite oxidising agent selected from hydrogen peroxide, TEMPO (2,2,6,6- Tetramethylpiperidinyloxy) or mixture in the presence of phase transfer catalyst or transition metal catalyst.
IN3670/CHE/2013 discloses a process for the preparation of ferric carboxymaltose complex by reacting an aqueous solution of ferric chloride with aqueous solution of oxidised maltodextrin wherein the oxidation is carried out using organic hypo halite (tert-butyl hypochlorite) in the presence of transition metal catalyst or alkali halide catalyst and phase transfer catalyst.
IN370845 discloses a process for the preparation of ferric carboxymaltose complex by reacting ferric hydroxide suspension with maltodextrin followed by oxidizing maltodextrin with citric acid further reaction with ammonia to provide ferric carboxymaltose.
IN201841012945 discloses a process for preparation of ferric carboxymaltose complex by oxidizing one or more maltodextrins with oxone further reacting the oxidized maltodextrins with iron (III) salt to provide ferric carboxymaltose.
The present inventors have developed an improved industrially viable process which does not involve the usage of any toxic and/or costly solvents or reagents, metals and critical workup procedures. Accordingly, the present invention provides an improved process for the preparation of Ferric carboxymaltose, which is simple, efficient, cost effective, environmentally friendly and commercially scalable for large scale operations with excellent yields and good quality.

Summary of the invention
The first embodiment of the present invention provides a process for the preparation of Ferric carboxymaltose.

Detailed description of the invention
The term "solvent" used in the present invention refers to "ketone solvents" selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and thereof;"alcoholic solvents" selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol or mixtures thereof; "polar solvents" selected from water or mixtures thereof.
The term "base" used in the present invention selected from but not limited to inorganic acids selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like;
The term "room temperature" as used in the present invention herein refers to the temperature in the range from about 25-35°C.

The first embodiment of the present invention provides a process for the preparation of Ferric carboxymaltose, comprising: reacting oxidized one or more maltodextrins with ferric oxyhydroxide wherein oxidation of one or more maltodextrins is carried out using bromine solution at alkaline pH to provide Ferric carboxymaltose.
In first aspect of first embodiment, when one maltodextrin is present, the maltodextrin has a dextrose equivalent of between 16 and 24, and when a mixture of more than one maltodextrins are present, the dextrose equivalent of each individual maltodextrin is between 5 and 40, and the dextrose equivalent of the
mixture is between 16 and 24.
In second aspect of first embodiment, oxidation of one or more maltodextrins is carried out by using bromine solution at alkaline pH range from about 8 to 12 and temperature ranges from about 15°C to 100°C. Preferably from about 25°C to 55°C.
In third aspect of first embodiment, ferric oxyhydroxide is reacting with the solution of oxidized one or more maltodextrins at alkaline pH range from about 8 to 12 and temperature ranges from about 20°C to 100°C to provide Ferric carboxymaltose.
In fourth aspect of first embodiment, ferric oxyhydroxide is prepared by reacting iron (III) salt in aqueous medium at alkaline pH range from about 8 to 12 and temperature ranges from about 15°C to 70°C. Preferably from about 25°C to 35°C.
Where in iron (III) salt is selected from water soluble inorganic or organic acids salts of iron or mixtures thereof, such salt selected from not limited to iron chloride and iron bromide or iron citrate or like salts. Preferably iron (III) chloride.
In fifth aspect of first embodiment, after completion of the reaction, the reaction mixture is cooled to room temperature, pH was adjusted to 5.5- 6.5 by adding dilute hydrochloride solution and filtered through 0.2 micron filter. After filtration, product was precipitated by using alcohol solvent. After isolation optionally washed the product with alcohol solvent or ketone solvent or mixture thereof and dried the product by any conventional methods known in the art.
In sixth aspect of first embodiment, Ferric carboxymaltose complex obtaining from present invention having an average molecular weight of 80 kDa to 400 kDa. Preferably 130 kDa to 350 kDa.
In seventh aspect of first embodiment, the iron content of the obtained Ferric carboxymaltose complex is 20 to 40% weight/weight, preferably 28 to 34% weight/weight. Chloride content in obtained Ferric carboxymaltose complex is not more than 1% weight/weight. Osmolarity of obtained Ferric carboxymaltose complex is not more than 400 mOsmol/L. Average core particle size of iron in Ferric carboxymaltose complex is 20-30 nm, Preferably 26.2 nm
Another embodiment of present invention, Ferric carboxymaltose complex obtained from the present invention can be used for the treatment of iron deficiency anemia.
Molecular weight of the Ferric carboxymaltose complex is measured by gel permeation chromatography, (e.g. as described by Geisser et al., in Arzneim. Forsch/Drug Res. 42(II), 12, 1439-1452 (1992), paragraph 2.2.5). Dextrose equivalent measured gravimetrically with aqueous solution Fehling's solution. Iron content and chloride content are measured by complexometry and potentiometry respectively. Osmolality is measured by using Osmometer. Average core particle size of iron in the complex was measured by conventional Dynamic Light Scattering (DLS) method.

Starting material(s) utilized in the present invention are commercially available in the market (or) they can be prepared according to the any of the processes known in the prior art.

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are for illustrative purposes only and in no way limit the scope of the present invention.
Examples:
Example 1: Preparation of ferric carboxymaltose
Step (i)
40% ferric chloride solution (108 kg) was added to purified water (594 L) at room temperature and stirred of 10 minutes at same temperature. Cooled the above solution to 0-5°C. pH of solution was adjusted to 6-7 by adding 10% sodium carbonate solution. Stirred the mixture for one hour at 0-5°C. Filtered the solid, and directly used for the next step without purification.
Step (ii)
2% Bromine solution was added to the solution of purified water (35 L) and maltodextrin (35 kg) at room temperature and stirred of 30 minutes at same temperature. pH of the mixture was adjusted to 10.9 to 11.5 by adding 50% sodium hydroxide solution. Heated the reaction mixture to 40-45°C and stirred for 3 hour at same temperature. Wet solid obtained in step (i) was added to mixture with stirring. Maintained the pH of the reaction mixture 11 by using 50% sodium hydroxide solution. Heated the reaction mixture to 95-100°C and stirred for 15 minutes at same temperature. Cooled the reaction mixture to room temperature and pH was adjusted to 5.5- 6.5 by adding dilute hydrochloride solution. Heated the reaction mixture to 50-55°C and stirred for 30 minutes at same temperature. Cooled the reaction mixture to room temperature and filtered through 0.2 micron filter. Compound was precipitated by using ethanol solution. Filtered the solid and washed with ethanol and acetone. Dried under vacuum to get titled compound.
Average molecular weight: 150 kDa; Iron content: 26.4 weight/weight; Core particle sizes of iron: 25.4 nm; Chloride content: 0.2%; Osmolality: 392 mOsmol/L.

Example 2: Preparation of ferric carboxymaltose
2% Bromine solution was added to the solution of purified water (35 L) and maltodextrin (35 kg) at room temperature and stirred of 30 minutes at same temperature. pH of the mixture was adjusted to 10.9 to 11.5 by adding 50% sodium hydroxide solution. Heated the reaction mixture to 40-45°C and stirred for 3 hour at same temperature. Wet solid obtained in step (i) of example 1 was added to mixture with stirring. Maintained the pH of the reaction mixture 11 by using 50% sodium hydroxide solution. Heated the reaction mixture to 95-100°C and stirred for 30 minutes at same temperature. Cooled the reaction mixture to room temperature and pH was adjusted to 5.5- 6.5 by adding dilute hydrochloride solution. Heated the reaction mixture to 50-55°C and stirred for 30 minutes at same temperature. Cooled the reaction mixture to room temperature and filtered through 0.2 micron filter. Compound was precipitated by using ethanol solution. Filtered the solid and washed with ethanol and acetone. Dried under vacuum to get titled compound.
Average molecular weight: 180 kDa; Iron content: 30.2 weight/weight; Core particle sizes of iron: 26.2 nm; Chloride content: 0.2%; Osmolality: 357 mOsmol/L.
Example 3: Preparation of ferric carboxymaltose
2% Bromine solution was added to the solution of purified water (35 L) and maltodextrin (35 kg) at room temperature and stirred of 30 minutes at same temperature. pH of the mixture was adjusted to 10.9 to 11.5 by adding 50% sodium hydroxide solution. Heated the reaction mixture to 40-45°C and stirred for 3 hour at same temperature. Wet solid obtained in step (i) of example 1 was added to mixture with stirring. Maintained the pH of the reaction mixture 11 by using 50% sodium hydroxide solution. Heated the reaction mixture to 95-100°C and stirred for 60 minutes at same temperature. Cooled the reaction mixture to room temperature and pH was adjusted to 5.5- 6.5 by adding dilute hydrochloride solution. Heated the reaction mixture to 50-55°C and stirred for 30 minutes at same temperature. Cooled the reaction mixture to room temperature and filtered through 0.2 micron filter. Compound was precipitated by using ethanol solution. Filtered the solid and washed with ethanol and acetone. Dried under vacuum to get titled compound.
Average molecular weight: 260 kDa; Iron content: 33.9 weight/weight; Core particle sizes of iron: 26.6 nm; Chloride content: 0.2%; Osmolality: 346 mOsmol/L.
Example 4: Preparation of ferric carboxymaltose
2% Bromine solution was added to the solution of purified water (35 L) and maltodextrin (35 kg) at room temperature and stirred of 30 minutes at same temperature. pH of the mixture was adjusted to 10.9 to 11.5 by adding 50% sodium hydroxide solution. Heated the reaction mixture to 40-45°C and stirred for 3 hour at same temperature. Wet solid obtained in step (i) of example 1 was added to mixture with stirring. Maintained the pH of the reaction mixture 11 by using 50% sodium hydroxide solution. Heated the reaction mixture to 95-100°C and stirred for 90 minutes at same temperature. Cooled the reaction mixture to room temperature and pH was adjusted to 5.5- 6.5 by adding dilute hydrochloride solution. Heated the reaction mixture to 50-55°C and stirred for 30 minutes at same temperature. Cooled the reaction mixture to room temperature and filtered through 0.2 micron filter. Compound was precipitated by using ethanol solution. Filtered the solid and washed with ethanol and acetone. Dried under vacuum to get titled compound.
Average molecular weight: 350 kDa; Iron content: 32.6 weight/weight; Core particle sizes of iron: 25.9 nm; Chloride content: 0.3%; Osmolality: 338 mOsmol/L.