WO2018198135A1

WO2018198135A1 - Improved process for the preparation of iron complex

Info

Publication number: WO2018198135A1
Application number: PCT/IN2018/050250
Authority: WO
Inventors: Sureshbabu JAYACHANDRA; Sonny Sebastian; Jayaprakash Thirunavukarasu; Rajakrishna Yerramalla; Jaganmohanarao BONTALAKOTI
Original assignee: Mylan Laboratories Ltd.
Priority date: 2017-04-26
Filing date: 2018-04-25
Publication date: 2018-11-01

Abstract

The present invention relates to an improved process for the preparation of Iron dextran & Sodium ferric gluconate, which is reproducible, easy to prepare on an industrial scale, and consistent in molecular weight range.

Description

IMPROVED PROCESS FOR THE PREPARATION OF IRON COMPLEX CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of Indian provisional patent application No. 201741014780 filed on April 26, 2017.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparing Iron complexes. BACKGROUND OF THE INVENTION

Iron is important for many functions in the body, especially for the transport of oxygen in the blood. Those suffering from iron deficiencies often require external supplementation of this vital mineral.

One source by which iron can be supplemented is through iron dextran, which is a complex of ferric oxide and dextran, and has been known for about 35 years. Iron dextran is used to treat iron deficiencies and iron deficiency anemia.

US2885393 first disclosed a basic process for the preparation of iron dextran complex in which the average molecular weight of the dextran is 30,000 to 80,000 Daltons (Da) or lower.

US6977249B1, which is incorporated here for reference, disclosed process for the preparation of iron dextran.

US576715, which is incorporated here for reference, also disclosed process for the preparation of iron dextran.

Another form of supplemental iron is sodium ferric gluconate, chemically known as D-gluconic acid iron sodium salt. Sodium ferric gluconate complex is approved under the trade name Ferrlecit by the United States Food and Drug Administration (USFDA). Sodium ferric gluconate complex is an intravenously administered iron product indicated in the treatment of iron deficiency anemia. It is frequently used in patients undergoing hemodialysis, those undergoing erythropoietin therapy, and/or patients who have chronic kidney disease. US7179939 which is incorporated here for reference, disclosed process for the preparation of sodium ferric gluconate.

PCT Publication No. WO2005111052, which is incorporated here for reference, also disclosed process for the preparation of sodium ferric gluconate comprises.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 1, JANUARY 2010 which is incorporated here for reference, also disclosed process for the preparation of sodium ferric gluconate.

Still there exists a need in the art for a method of preparation of substantially pure iron complexes that can be scaled for use in industry. In particular, the removal of inorganic salts and other soluble process impurities is desired. Thus, the present invention provides an improved process that is stable, reproducible, easy to prepare on an industrial scale, and consistent in quality and molecular weight range.

SUMMARY OF THE INVENTION: The present invention relates to an improved process for the preparation of Iron complexes.

In one aspect, the present invention relates an improved process for the preparation of stable ferric oxy hydroxide.

In yet another aspect the present invention relates to an improved process for the preparation of Iron dextran. a) reacting water soluble of iron (III) salt with an inorganic base

b) adding oxidized dextran

c) adding a base,

heating and cooling the reaction mass

e) adjusting the pH of the reaction mass,

f) adding second lot of dextran,

g) Isolating Iron dextran. In yet another aspect the present invention relates to a one stage process for the preparation of Sodium ferric gluconate. a) reacting water soluble of iron (III) salt with an inorganic base

b) adding a second base

c) adding gluconic acid derivative

d) heating the reaction mass,

e) adjusting the pH of the reaction mass,

f) adding second lot of gluconic acid derivative

g) Isolating Sodium ferric gluconate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for the preparation of Iron complexes.

In one embodiment, the present invention provides an improved process for the preparation of Iron dextran comprising the steps of: a) reacting a water-soluble iron (III) salt with an inorganic base

b) adding oxidized dextran

c) adding a base

d) heating the reaction mass

e) cooling the reaction mass

f) adding an anti solvent

g) isolating Iron dextran.

According to the present invention, Iron dextran may be prepared by reacting a water-soluble salt of iron(III) with an inorganic base in water. Examples of suitable water-soluble salts of iron(III) include iron(III) bromide, iron(III) chloride, iron(III) iodide, iron(III) nitrate, iron(III) sulfate, or any solvates thereof (e.g., iron(III) chloride hexahydrate). Examples of suitable inorganic bases include any that facilitate the formation of iron(III) hydroxide, for example, sodium carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide. One of skill in the art will readily predict what inorganic bases will result in the formation of iron(III) hydroxide, in particularly useful embodiments, an aqueous iron(III) chloride hexahydrate solution is added to an aqueous sodium carbonate solution to form an iron(III) hydroxide solution.

Next, oxidized dextran may be added which is optionally purified. Within the context of this embodiment, the dextran may have an average molecular weight of about 5000 daltons to about 10000 daltons. If the pH is not at a pH of 10-13, the pH of the reaction mass may be adjusted to 10 - 13 using a base. This adjustment may be carried out using methods well known by those skilled in the art (i.e., using appropriate acid or base). The reaction mass may then be heated, for example, to 90-100°C, and maintained at an elevated temperature for an extended period of time, for example, for about 2 hours.

Next, iron dextran may be isolated. This may be carried out by methods well known by one of skill in the art. For example, in some embodiments, precipitation of the iron dextran may be facilitated by cooling the reaction mixture and adding methanol. The precipitated solid may be isolated by filtering the reaction mixture then optionally dried to obtain the desired product.

By one method, Iron dextran can be isolated by initially adjusting the pH of the reaction mixture which is cooled after heating and spray dried.

In yet one embodiment, the present invention provides an improved process for the preparation of Iron dextran comprising the steps of: a) reacting a water-soluble iron (III) salt with an inorganic base

b) adding oxidized dextran

c) adjusting the pH of the reaction mass to 10 - 13

d) heating and cooling the reaction mass

e) adjusting the pH of the reaction mass to

f) adding second lot of dextran

g) Isolating Iron dextran.

According to the present invention, Iron dextran may be prepared by reacting a water-soluble salt of iron(III) with an inorganic base. Examples of suitable water-soluble salts of iron(III) include iron(III) bromide, iron(III) chloride, iron(III) iodide, iron(III) nitrate, iron(III) sulfate, or any solvates thereof (e.g., iron(III) chloride hexahydrate). Examples of suitable inorganic bases include any that result in the formation of iron(III) hydroxide, for example, sodium carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide. One of skill in the art will readily predict what inorganic bases will result in the formation of iron(III) hydroxide. In particularly useful embodiments, an aqueous iron(III) chloride hexahydrate solution is added to an aqueous sodium carbonate solution to form an iron(III) hydroxide solution.

Next, oxidized dextran may be added. Within the context of this embodiment, the dextran may have an average molecular weight of about 5000 daltons to about 10000 daltons. If the pH is not at a pH of 10 - 13, the pH of the reaction mass may be adjusted to 10 - 13 using a base. This adjustment may be carried out using methods well known by those skilled in the art (i.e., using appropriate acid or base). The reaction mixture may be cooled and the pH adjusted to 4-5 (using appropriate acid such as hydrochloric acid) and optionally purified.

In yet another method, after the Purification can be carried out by methods well known in the art, for example, by ultrafiltration, diafiltration, ion exchange, dialysis, or any combination thereof. In particularly useful embodiments, filtration is carried out by ultrafiltration. In some embodiments, maintaining the reaction mixture before undertaking subsequent steps for about 1-2 hours is particularly useful.

A second lot of dextran [may be oxidized or reduced] may then be added to the purified solution and the temperature may be optionally adjusted to 60-80 °C and maintained at that temperature for an extended period of time, e.g., for about 3-4 hours. Within the context of this embodiment, the second lot of dextran added may be oxidized dextran, reduced dextran, or a mixture of oxidized and reduced dextran. Further, the second lot of dextran may have an average molecular weight of about 5000 Daltons to about 10000 Daltons.

Next, iron dextran may be isolated, for example, by removal of the solvent or by causing precipitation of the iron dextran compound. Methods well known by one of skill in the art, e.g., distillation, spray drying, freeze drying may be used to carry out this isolation step.

Oxidized dextran may be prepared by methods well known in the art. For example, an aqueous solution of dextran and sodium hydroxide and may be combined with an aqueous solution of sodium hypochlorite. In some embodiments, this reaction is carried out for about 6 hours. Reduced dextran may be prepared by methods well known in the art. For example, an aqueous solution of dextran and sodium hydroxide may be combined with sodium borohydride dissolved in dilute sodium hydroxide. In some embodiments, this reaction is carried out for about 3-4 hours. Isolation of the reduced dextran may be carried out by methods well known in the art, for example, by filtering the solution and adding methanol to form a solid. The solution may then be filtered to obtain a solid, which may be optionally dried to obtain the desired product.

In yet another embodiment, the present invention provides an improved process for the preparation of sodium ferric gluconate, which includes the following steps: a) reacting an aqueous solution iron(III) chloride hexahydrate with an inorganic base b) adding a second base

c) adding a gluconic acid derivative

heating the reaction mass

e) adjusting the pH of the reaction mass

f) Isolating sodium ferric gluconate

According to the present invention, sodium ferric gluconate may be prepared by first reacting an aqueous solution of iron(III) chloride hexahydrate with an inorganic base. Examples of suitable inorganic bases include sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, ammonium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, rubidium hydroxide, cesium hydroxide, and mixtures thereof. In particularly useful embodiments, sodium hydroxide is used as the inorganic base.

Next, a second base may be added to the reaction mixture, followed by addition of a derivative of gluconic acid. In some embodiments, the reaction mixture is maintained for some time, e.g., 2-3 hours, before addition of the gluconic acid derivative. Examples of suitable gluconic acid derivatives include alkali earth metal salts of gluconic acid. In particularly useful embodiments, sodium gluconate is used. The reaction mixture may then be heated. In some embodiments, heating the reaction mixture to a temperature of about 100°C may be particularly useful. In some embodiments, maintaining the reaction mixture at this elevated temperature for about 4 to about 6 hours may be particularly useful. Next, the reaction mixture may be cooled and the pH may be adjusted to about 6 to about 9 using methods well known in the art (i.e., addition of an acid or a base). In particularly useful embodiments, the pH is adjusted to about 7 to about 8.

Next, the reaction mixture may optionally be purified. Purification can be carried out by methods well known in the art, for example, by diafiltration, ultrafiltration, ion exchange, dialysis, or any combination thereof. In particularly useful embodiments, filtration is carried out by ultrafiltration. In some embodiments, maintaining the reaction mixture before undertaking subsequent steps for about 1-2 hours is particularly useful.

Sodium ferric gluconate may then be isolated. Next, sodium ferric gluconate may be isolated by methods well known in the art. For example, precipitation may be initiated by the addition of an anti-solvent In some embodiments, ethanol is found to be a particularly useful anti-solvent while acetone and methanol can also be used as anti-solvents. The precipitated solid may be isolated by filtration and dried to obtain the desired product.

In some embodiments, after the pH is adjusted to 7 to about 8, the solid formed is filtered and washed with an alcoholic solvent preferably ethanol to obtain sodium ferric gluconate complex.

In yet another embodiment, the present invention provides an improved process for the preparation of sodium ferric gluconate comprising the steps of a) reacting water soluble of iron (III) salt with an inorganic base

b) adding a second base

c) adding gluconic acid derivative

d) heating the reaction mass,

e) adjusting the pH of the reaction mass

f) adding second lot of gluconic acid derivative

g) Isolating sodium ferric gluconate

Next, a second base may be added to the reaction mixture, followed by addition of a derivative of gluconic acid. In some embodiments, the reaction mixture is maintained for some time, e.g., 2-3 hours, before addition of the gluconic acid derivative. Examples of suitable gluconic acid derivatives include alkali earth metal salts of gluconic acid. In particularly useful embodiments, sodium gluconate is used. Optionally sucrose may also be added.

The reaction mixture may then be heated. In some embodiments, heating the reaction mixture to a temperature of about 100°C may be particularly useful. In some embodiments, maintaining the reaction mixture at this elevated temperature for about 4 to about 6 hours may be particularly useful. Next, the reaction mixture may be cooled and, if needed, the pH may be adjusted to about 6 to about 9 using methods well known in the art (i.e., addition of an acid or a base). In particularly useful embodiments, the pH is adjusted to about 7 to about 8.

Next, the reaction mixture may optionally be purified. Purification can be carried out by methods well known in the art, for example, by diafiltration, ultrafiltration, ion exchange, dialysis or any combination thereof. In particularly useful embodiments, filtration is carried out by ultrafiltration. In some embodiments, maintaining the reaction mixture before undertaking subsequent steps for about 1-2 hours is particularly useful.

A second lot of gluconic acid derivative may then be added. After adding the second lot of gluconic acid derivative, the pH may be adjusted to about 9 - 10.

Next, sodium ferric gluconate may be isolated by methods well known in the art. For example, precipitation may be initiated by the addition of an anti-solvent, for example an alcohol. Examples of suitable alcohol anti-solvents include ethanol, methanol, or mixtures thereof. In some embodiments, ethanol is found to be a particularly useful anti-solvent while acetone and methanol can also be used as anti-solvents. The precipitated solid may be isolated by filtration and optionally dried to obtain the desired product.

In some embodiments, processes disclosed herein may have the following advantages over prior art: a) One stage process for preparing iron complexes.

b) Process is reproducible and scalable.

c) Consistent in quality and molecular weight range.

d) Controlling inorganic salts from product by ultrafiltration through membrane. The following examples are provided to illustrate the process of the present invention. They, are however, not intended to limiting the scope of the present invention in any way and several variants of these examples would be evident to person ordinarily skilled in the art.

EXAMPLES Example-1 A mixture of Ferric chloride hexahydrate (100 g, 0.369 mole) in water (1000 ml) was stirred at room temperature for 10-20 minutes. Sodium carbonate solution (56 g, 0.528 mole) in water (200ml) was added to mixture at 25-35°C in lot wise and stirred for 110-120 minutes. Sodium hydroxide solution (6 g, 0.15 mole) in water (50ml) was added to reaction mixture and stirred for 1-2 hours. A solution of Sodium gluconate (40 g, 0.183 mole) was added to the mixture followed by water (50ml) and heated to 98-100°C and stirred for 4-6 hours. Reaction mixture was cooled to room temperature and adjusted the pH-7.0-8.0. Ethanol (7000 ml) was added to the reaction mixture and the precipitated solid was isolated by filtration. The product was dried under vacuum at 60-70°C to get sodium ferric gluconate. Molecular weight by gel Permeation chromatography: 402536 Da Example-2

A solution of Sodium carbonate solution (56 g, 0.528 mole) in water (200ml) was added to a solution of Ferric chloride hexahydrate (100 g, 0.369 mole) in water (1000 ml at room temperature for 10-20 minutes. The reaction mixture was stirred for 110-120 minutes and Sodium hydroxide solution (6 g, 0.15 mole) in water (50ml) was added and stirred further for 1-2 hours. Sodium gluconate (40 g, 0.183 mole) followed by water (50ml) was added to the mixture and heated to 98- 100°C for 4-6 hours. The reaction mass was cooled to room temperature and adjusted pH-7.0-8.0. The solution was filtered by ultrafiltration using membrane. Filtrate was collected and sodium gluconate (34g, 0.156 moles) was added and the mixture was stirred 1-2 hours. pH was adjusted to 9.0-9.5 and added ethanol (3500ml). Precipitated product was filtered and washed with ethanol - water mixture and dried under vacuum at 60±5°C to get sodium ferric gluconate. Molecular weight by gel Permeation chromatography: 441558 Da.

Example - 3 A solution of Ferric chloride hexahydrate (100 g, 0.369 mole) in water (1000 ml) was mixed with a solution of Sodium carbonate solution (56 g, 0.528 mole) in water (200ml) and stirred at room temperature for 110-120 minutes. The resulting solid was collected by filtration and washed with water (1000ml). Above obtained solid was mixed water (600 ml) and stirred with sodium hydroxide solution (6 g, 0.15 mole) in water (50ml) and stirred 1-2 hours. Sodium gluconate (40 g, 0.183 mole) and water (50ml) were added to the mixture and heated to 98-100°C for 4-6 hours and cooled to room temperature. pH was adjusted to 7.0-8.0 and the precipitated product filtered and washed with Ethanol (7000 ml) and dried under vacuum at 60±5°C to get sodium ferric gluconate. Molecular weight by gel Permeation chromatography: 552247 Da

Example-4 Sodium carbonate solution (56 g, 0.528 mole) in water (200ml) was added in lot wise to a mixture of Ferric chloride hexahydrate (100 g, 0.369 mole) in water (1000 ml) was stirred at room temperature for 10-20 minutes and further stirred for 1-2 hours. Sodium hydroxide solution (6 g, 0.15 mole) in water (50ml) was charged to reaction mixture followed by Sodium gluconate (40 g, 0.183 mole) and sucrose (300g, 0876 moles). The mixture was heated to 98-100°C and maintained for 4-6 hours. Reaction mixture was cooled to room temperature and adjusted in between pH-7.0- 8.0. The solution was filtered by ultrafiltration using membrane. Filtrate was collected and added sodium gluconate (34g, 0.156 moles) and stirred for stirred 1-2 hours and adjusted in between pH- 9.0-9.5. Ethanol (3500ml) was added to the reaction mixture and resulting crystalline solid was collected by filtration and washed with ethanol-water mixture. The wet product was dried under vacuum at 60-70°C to get sodium ferric gluconate. Molecular weight by gel Permeation chromatography: 483269 Da

Example- 5 A mixture of Dextran-5 (Average Molecular weight 5000) (100 g, 0.02 mole) and sodium hydroxide (0.5 g, 0.01 mole) in water was stirred at room temperature at RPM 30-50 for 30 minutes. Sodium hypo chlorite solution ( 100 ml, 0.15 mole) was added to the mixture. The reaction mixture was stirred at room temperature for 6 hours. A solution of sodium carbonate (24 g, 0.2264 mole) in water (100 ml) was added a solution of Ferric chloride hexahydrate (100 g, 0.369 mole) and water (500 ml) and the resulting reaction mass was added to the above reaction mixture. The reaction mass was basified with aqueous sodium hydroxide solution and heated at 95°C for 2 hours. The reaction mixture was cooled to ambient temperature and concentrated to a volume 650 ml. Methanol was added with stirring. The resulting crystalline solid was collected by filtration and washed with methanol. The obtained solids were dried under vacuum at 45-50oC to get Iron Dextran. Mol wt (by Gel Permeation chromatography): 141 KDa

Example- 6

A mixture of dextran- 5 (Average Molecular weight 5000) (100 g, 0.02 mole) and sodium hydroxide (0.5 g, 0.01 mole) in water was stirred at room temperature for 30 minutes. Sodium hypo chlorite solution (100 ml, 0.15 mole) was added mixture. The reaction mixture was stirred at room temperature for 6 hours. The solution was purified using membrane process (dia filtration). Another mixture of Ferric chloride hexahydrate (100 g, 0.369 mole) and water (500 ml) a solution of sodium carbonate (24 g, 0.2264 mole) in water ( ml) and stirred for 10-20 minutes (RPM 80- 100). This reaction mixture was mixed with above prepared reaction mass and basified with sodium hydroxide solution. The obtained mixture was heated at 95°C for 2 hours and cooled to an ambient temperature and acidified pH 4-5 using Hydrochloric acid. The solution was purified using membrane process (dia filtration). The solution was spray dried to get Iron Dextran powder.

Mol wt (by Gel Permeation chromatography): 136 KDa

Example-7 A mixture of dextran -5 (Average Molecular weight 5000) (100 g, 0.02 mole) and sodium hydroxide (0.5 g, 0.01 mole) in water was stirred (RPM 30-50) at room temperature for 30 minutes. Sodium hypo chlorite (100 ml, 0.15 mole) was added mixture. The reaction mixture was stirred at room temperature for 6 hours. The solution was purified using membrane process (dia filtration). Another mixture of Ferric chloride hexahydrate (100 g, 0.369 mole) was dissolved water (500 ml) and added a solution of sodium carbonate (24 g, 0.2264 mole) in water to it and stirred for 15-20 minutes (RPM 80-100). This reaction mass was mixed with above obtained Dextran reaction mass and the resulting mixture was basified with a solution of sodium hydroxide. The obtained mixture was heated at 95 -100 °C for 2 hours and cooled to an ambient temperature and acidified pH 4-5 using Hydrochloric acid. Solution was concentrated by distillation to a volume 650 ml and then stirred with methanol. The resulting crystalline solid was collected by filtration and washed with methanol. The obtained solid was dried under vacuum to get Iron Dextran.

Mol wt (by Gel Permeation chromatography): 135KDa

Example-8 A mixture of dextran -5 (Average Molecular weight 5000) (100 g, 0.02 mole) and sodium hydroxide (1.0 g, 0.02 mole) in water was stirred at room temperature for 30 minutes. Sodium hypochlorite (50ml, 0.075 mole) was added and stirred at room temperature for 6 hours. The solution was purified using membrane process (dia filtration). Another mixture of Ferric chloride hexahydrate (100 g, 0.369 mole) and water (500 ml) was mixed with a solution of sodium carbonate (24 g, 0.2264 mole) in water and added to the above obtained Dextran reaction mass. To the resulting mixture added a solution of sodium hydroxide to attain basic pH. The obtained mixture was maintained at 95-100°C for 120 minutes and cooled to an ambient temperature and acidified to pH4-5 using Hydrochloric acid. Solution was concentrated to a volume 650 ml and then added to methanol with stirring. The resulting crystalline solid was collected by filtration and washed with methanol. The obtained solids were dried under vacuum to get iron dextran solids.

Mol wt (by Gel Permeation chromatography): 140 KDa Example-9

A mixture of dextran-5 (Average Molecular weight 5000) (100 g, 0.02 mole) and sodium hydroxide (1.0 g, 0.02 mole) in water was stirred at room temperature for 30 minutes. Sodium hypo chlorite (50ml, 0.075 mole) was added the reaction mixture was stirred at room temperature for 6 hours. Another mixture of Ferric chloride hexahydrate (100 g, 0.369 mole) and water (500 ml) was mixed with a solution of sodium carbonate (24 g, 0.2264 mole) in water. After stirring for 10-20 minutes, the reaction mixture was mixed with above obtained Dextran reaction mass. To the resulting mixture was added a solution of sodium hydroxide to attain basic pH to 10-13. The obtained mixture was heated at 90-100°C for 2-3 hours and cooled to an ambient temperature and acidified pH-4.0 using Hydrochloric acid. Solution was concentrated to a volume 650 ml and then added with stirring to methanol. The resulting crystalline solid was collected by filtration and washed with methanol. The obtained solids were dried under vacuum to get Iron Dextran.

Gel Permeation chromatography: 126kda

Example-10

A mixture of dextran grade 5 (Average Molecular weight 5000) (100 g, 0.02 mole) and sodium hydroxide (1.0 g, 0.02 mole) in water was stirred at room temperature for 30 minutes. Sodium hypo chlorite (150ml, 0.225 mole) was added to the mixture. The reaction mixture was stirred at room temperature for 6 hours. Another mixture of Ferric chloride hexahydrate (100 g, 0.369 mole) solution in water (500 ml) was mixed a solution of sodium carbonate (24 g, 0.2264 mole) in water followed by addition of above obtained Dextran reaction mass and the resulting mixture was basified with a solution of sodium hydroxide. The obtained mixture was maintained at 95-100°C for 2 hours and cooled to an ambient temperature and acidified pH-4.0 using Hydrochloric acid. Solution was concentrated to a volume of about 700 ml and then added to methanol with stirring. The resulting crystalline solid was collected by filtration and washed with methanol. The obtained solids were dried under vacuum to get Iron Dextran. Mol wt (by Gel Permeation chromatography): 116 kda Example- 11

A mixture of dextran grade 10 (Average Molecular weight 10000) (100 g, 0.01 mole) and sodium hydroxide (0.5 g, 0.01 mole) in water was stirred at room temperature for 30 minutes. Sodium hypo chlorite (100 ml, 0.15 mole) was added mixture. The reaction mixture was stirred at room temperature for 6 hours. Another mixture of Ferric chloride hexahydrate (100 g, 0.369 mole) and water (500 ml) a solution of sodium carbonate (24 g, 0.2264 mole) in water was added followed by addition of above obtained Dextran reaction mass. To the resulting mixture was added a solution of sodium hydroxide to basify to about 11 pH. The obtained mixture was heated at 90o-100°C for 2 hours and cooled to an ambient temperature and acidified to pH4-5 using Hydrochloric acid. Solution was concentrated to a about 700 ml and then added to methanol. The resulting crystalline solid was collected by filtration and washed with methanol. The obtained solid was dried under vacuum to get Iron Dextran. Mol wt (Gel Permeation chromatography): 196 kda

Example- 12

A mixture of dextran -5 (Average Molecular weight 5000) (100 g, 0.02 mole) and sodium hydroxide (0.5 g, 0.01 mole) in water (300 ml) was stirred at room temperature for 30 minutes. Sodium hypo chlorite solution (65 ml, 0.09 mole) was added mixture. The reaction mixture was stirred at room temperature for 6 hours. Another solution of Ferric chloride hexahydrate (100 g, 0.369 mole) in water (500 ml) was mixed with a solution of sodium carbonate (24 g, 0.2264 mole) in water and was stirred for 10-20 minutes. The resulting reaction mass was mixed with the above obtained Dextran reaction mass. To the resulting mixture added a solution of sodium hydroxide to attain basic pH (11-12). The obtained mixture was heated at 90-100°C for 2-3 hours and cooled to an ambient temperature and acidified pH4-5 using Hydrochloric acid. The solution was purified using membrane process (dia filtration). Reduced dextran (60 g) was added to the purified solution at pH 5 to 6.5 and heated to 70-80° C solution for 2-3 hours. Iron Dextran was isolated as a solid from the reaction mass by spray drying. Mol wt (by Gel Permeation chromatography): 136 kda

Example- 13

A mixture of dextran -5 (Average Molecular weight 5000) (100 g, 0.02 mole) and sodium hydroxide (0.5 g, 0.01 mole) in water (300 ml) was stirred at room temperature for 30 minutes. Sodium hypo chlorite solution (100 ml, 0.15 mole) was added mixture. The reaction mixture was stirred at room temperature for 6 hours. Another solution of Ferric chloride hexahydrate (100 g, 0.369 mole) in water (500 ml) was mixed with a solution of sodium carbonate (24 g, 0.2264 mole) in water and was stirred for 10-20 minutes. The resulting reaction mass was mixed with the above obtained Dextran reaction mass. To the resulting mixture added a solution of sodium hydroxide to attain basic pH (11-12). The obtained mixture was heated at 90-100°C for 2-3 hours and cooled to an ambient temperature and acidified pH4-5 using Hydrochloric acid. The solution was purified using membrane process (dia filtration). Oxidized dextran (60 g) was added to the purified solution at pH 5 to 6.5 and heated to 70-80° C solution for 2-3 hours. Iron Dextran was isolated as a solid from the reaction mass by spray drying. Example- 14

A mixture of dextran -5 (Average Molecular weight 5000) (100 g, 0.02 mole) and sodium hydroxide (0.5 g, 0.01 mole) in water (300 ml) was stirred at room temperature for 30 minutes. Sodium hypo chlorite solution (100 ml, 0.15 mole) was added mixture. The reaction mixture was stirred at room temperature for 6 hours. Another solution of Ferric chloride hexahydrate (100 g, 0.369 mole) in water (500 ml) was mixed with a solution of sodium carbonate (24 g, 0.2264 mole) in water and was stirred for 10-20 minutes. The resulting reaction mass was mixed with the above obtained Dextran reaction mass. To the resulting mixture added a solution of sodium hydroxide to attain basic pH (11-12). The obtained mixture was heated at 90-100°C for 2-3 hours and cooled to an ambient temperature and acidified pH4-5 using Hydrochloric acid. The solution was purified using membrane process (dia filtration). A mixture of Oxidized dextran (30 g) and reduced dextran (30 g) was added to the purified solution at pH 5 to 6.5 and heated to 70-80° C solution for 2-3 hours. Iron Dextran was isolated as a solid from the reaction mass by spray drying.

Example- 15 A mixture of dextran -5 (Average Molecular weight 5000) (100 g, 0.02 mole) and sodium hydroxide (0.5 g, 0.01 mole) in water (300 ml) was stirred at room temperature for 30 minutes. Sodium hypo chlorite solution (100 ml, 0.15 mole) was added mixture. The reaction mixture was stirred at room temperature for 6 hours. Another solution of Ferric chloride hexahydrate (100 g, 0.369 mole) in water (500 ml) was mixed with a solution of sodium carbonate (24 g, 0.2264 mole) in water and was stirred for 10-20 minutes. The resulting reaction mass was mixed with the above obtained Dextran reaction mass. To the resulting mixture added a solution of sodium hydroxide to attain basic pH (11-12). The obtained mixture was heated at 90-100°C for 2-3 hours and cooled to an ambient temperature and acidified pH4-5 using Hydrochloric acid. The solution was purified using membrane process (dia filtration). Dextran-5 (60 g) was added to the purified solution at pH 5 to 6.5 and heated to 70-80° C solution for 2-3 hours. Iron Dextran was isolated as a solid from the reaction mass by spray drying.

Example- 16

A mixture of dextran grade 10 (Average Molecular weight 10000) (100 g, 0.01 mole) and sodium hydroxide (1.0 g, 0.02 mole) in water was stirred at room temperature for 30 minutes. Sodium hypo chlorite (50ml, 0.075 mole) was added mixture. The reaction mixture was stirred at room temperature for 6 hours. The solution was purified using membrane process (dia filtration). Another mixture of Ferric chloride hexahydrate (100 g, 0.369 mole) and water (500 ml) a solution of sodium carbonate (24 g, 0.2264 mole) in water was added followed by above obtained Dextran reaction mass. To the resulting mixture was added a solution of sodium hydroxide to attain basic pH. The obtained mixture was heated at 95°C for 2 hours and cooled to an ambient temperature and acidified to pH 4-5 using Hydrochloric acid. Solution was concentrated to a volume 650 ml and then added with stirring to methanol. The resulting crystalline solid was collected by filtration and washed with methanol. The obtained solids were dried under vacuum to get iron dextran solids. Gel Permeation chromatography: 300kda

Example- 17

A mixture of dextran grade 3.5 (Average Molecular weight 3500) (100 g, 0.0285 mole) and sodium hydroxide (0.5 g, 0.01 mole) in water was stirred at room temperature for 30 minutes. Sodium hypo chlorite (100 ml, 0.15 mole) was added mixture. The reaction mixture was stirred at room temperature for 6 hours. The solution was purified using membrane process (dia filtration). Another mixture of Ferric chloride hexahydrate (100 g, 0.369 mole) and water (500 ml) was mixed a solution of sodium carbonate (24 g, 0.2264 mole) in water followed by addition of above obtained Dextran reaction mass. To the resulting mixture added a solution of sodium hydroxide to attain basic pH. The obtained mixture was heated at 90-100°C for 2 hours and cooled to an ambient temperature and acidified to pH 4-5 using Hydrochloric acid. The solution was purified using membrane process (dia filtration) and the purified solution was spray dried to get Iron Dextran powder. Gel Permeation chromatography: 106 kda

Example-18: Preparation of reduced dextran

A mixture of dextran grade 5 (Average Molecular weight 5000) (100 g, 0.02 mole) and sodium hydroxide (0.5 g, 0.01 mole) in water was stirred at room temperature for 30 minutes. Sodium borohydride (2 g, 0.05 mole) dissolved in dilute sodium hydroxide was added to reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. The solution was purified using membrane process (dia filtration). Purified solution was added to methanol with stirring. The resulting crystalline solid was collected by filtration and washed with methanol. The obtained solids were dried under vacuum to get reduced dextran as a solid. Dry weight 71.0 g

Example-19

A mixture of dextran-5 (Average Molecular weight 5000) (100 g, 0.02 mole) and sodium hydroxide (0.5 g, 0.01 mole) in water was stirred at room temperature for 30 minutes. Sodium borohydride (2 g, 0.05 mole) dissolved in dilute sodium hydroxide was added to reaction mixture. The reaction mixture was stirred at room temperature for 2 hours, pH of the reaction mass adjusted to 4.0 to 5.0 using Hydrochloric acid and solution was spray dried at 100°C. Dry weight 75.0 g

Claims

We claim:

1. A process for the preparation of iron dextran comprising the steps of:

a) reacting a water - soluble iron(III) salt with a base in water;

b) adding oxidized dextran;

c) adjusting the pH of the reaction mass to 10 - 13;

d) heating and cooling the reaction mass;

e) adjusting the pH of the reaction mass to 2.5 - 6.5;

f) adding second lot of dextran; and

g) isolating the iron dextran.

2. A process for the preparation of sodium ferric gluconate comprising the steps of:

a. reacting water soluble of iron (III) salt with an inorganic base

b. adding a second base

c. adding gluconic acid derivative;

d. heating the reaction mass;

e. adjusting the pH of the reaction mass;

f. adding second lot of gluconic acid derivative; and

g. isolating sodium ferric gluconate.

3. The process as claimed in claims 1 or 2, wherein the iron(III) salt is selected from the group consisting of iron(III) bromide, iron(III) chloride, iron(III) iodide, iron(III) nitrate, iron(III) sulfate, hydrates thereof, and mixtures thereof.

4. The process as claimed in claim 3, wherein the iron (III) salt is iron(III) chloride hexahydrate.

5. The process as claimed in claims 1 or 2, wherein the base is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, ammonium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, rubidium hydroxide, cesium hydroxide, and mixtures thereof.

6. The process as claimed in claim 5, wherein the base is sodium carbonate or sodium hydroxide.

7. The process as claimed in claim 1, wherein the second lot of dextran is oxidized or reduced dextran.

8. The process as claimed in claim 1, wherein the dextran has an average molecular weight of about 5000 Daltons to about 10000 Daltons.

9. The process as claimed in claim 1, wherein the iron dextran has an average molecular weight of about 80 to 200 kilodaltons.

10. The process as claimed in claim 1, wherein the sodium ferric gluconate has an average molecular weight of about 350 to 600 kilodaltons.

11. The process as claimed in claims 1 or 2, wherein the isolation of iron dextran or sodium ferric gluconate is by spray drying.

12. The process as claimed in claims 1 or 2, wherein the dextran or the gluconic acid derivative is optionally purified by diafiltration, ultrafiltration, ion exchange, dialysis or any combination thereof.

13. The process as claimed in claims 12, wherein the purification is by ultrafiltration.