WO2009078037A2

WO2009078037A2 - Novel process for the preparation of iron sucrose complex

Info

Publication number: WO2009078037A2
Application number: PCT/IN2008/000807
Authority: WO
Inventors: Gollagunta Nadamuni; Chidamabram Subramaniyan Venkatesan; Surapanini Sridevi; Singaram Sathiyanarayanan; Karakala Sreekant Reddy; Akasapu Prem Sagar
Original assignee: Gland Pharma Limited
Priority date: 2007-12-17
Filing date: 2008-12-02
Publication date: 2009-06-25
Also published as: WO2009078037A3

Abstract

The present invention provides a novel reproducible method for the preparation of Iron sucrose complex using ferric acetate that is prepared freshly from ferric hydroxide. This method affords iron sucrose complex in a powder form and an injectable form.

Description

NOVEL PROCESS FOR THE PREPARATION OF IRON SUCROSE COMPLEX

FIELD OF INVENTION

The present invention is related to a novel process for manufacture of iron sucrose complex.

BACKGROUND OF THE INVENTION

Iron carbohydrate complexes, which have favourable properties for therapeutic use, are of great interest. Iron complexes with Dextran, Dextrose, maltose, Sucrose, Fructose are some of the important complexes.

Preparation of iron sucrose complex, complying with U.S. Pharmacopeia, having molecular weight between 34000 and 60000 Daltons, and structural formula [Na2Fe₅O₈ (OH).3(H2O)] n. m (C₁₂H₂₂O₁₁) is an important therapeutic complex widely used to treat anemia. Preparation of complexes of carbohydrates with iron compounds were disclosed in many patents and publications.

The Polish patent PL.45, 026, (1961) discloses a process for preparing complex of iron with carbohydrates like dextran, sucrose, and starch. By this process, iron sucrose complex was prepared by heating ferric hydroxide with sucrose in an alkali medium at 50 -6O⁰C and isolating the complex by precipitating with methanol or acetone.

US patent 3,821 ,192(1974) by Montgomery, et.al, discloses a process for preparing a stable, soluble complex of iron with glucose, maltose or dextrin. This, however, does not include sucrose. They used ferric hydroxide derived from ferric chloride and polymerised in presence of carbohydrate at pH 11.0-14.0

De Amdrosi, et.al US 4,746,730(1988), prepared iron saccharate and fructate by basifying aqueous ferric chloride and sucrose/fructose to pH 7.8-8.5 at room temperature. Mehansho et al, in their patent US 4,994,283(1991) disclosed a method for preparing iron-sugar complex This method involves preparation of complex of calcium with sugar. The calcium sucrose complex is further treated with ferrous ammonium sulfate and maleic acid to yield an iron-sugar complex. The multistep process is tedious and not convenient for the preparation of the complex in commercial quantities.

T. Ramesh baburao, in IN 187116(2002), disclosed a method for preparing saccharated iron oxide by reaction of aqueous solution of ferric hydroxide with sucrose at pH between 6.5 to 7.5.

WO 2005/094202 discloses a process for the preparation of iron sucrose complex which involves heating the aqueous solution of sucrose with ferric hydroxide at 100 -105⁰C.

WO 2005/000210 discloses a method for the preparation of Iron sucrose complex wherein a mixture of ferric chloride and sucrose is treated with sodium hydroxide solution to give ferric hydroxide sucrose complex. The disadvantage of this method is that the product formed may have lot of unchanged ferric salts.

Patent number WO 2006/061685 discloses the preparation of iron sucrose complex involving treatment of aqueous solution of sucrose with ferric hydroxide at 90-95⁰C.

It is an object of the present invention is to provide a novel process for the preparation of iron sucrose complex.

Another object of the present invention is to provide a simple, reproducible and industrially viable process for the preparation of the iron sucrose complex complying with U. S. Pharmacopeia. Summary:

Accordingly, one aspect of the present invention is a novel process for the preparation of iron sucrose complex comprising steps of: a) treating aqueous solution of ferric salt with a base to obtain ferric hydroxide wherein the pH is between 3.5 and 7.0 and temperature is between between 10° and 40⁰C. b) preparing ferric acetate from ferric hydroxide obtained in step (a) by treatment with acetic acid at a temperature between10° and 40°. c) treating sucrose with aqueous solution of ferric acetate or ferric hydroxide obtained in step (a) at 15°-40°C with the molar ratio of sucrose to ferric compound between 3.5 and 15 and the pH of the reaction mixture adjusted to between 9.5 and 12 using inorganic base followed by polymerization at 80-100⁰C. d) autoclaving the reaction mixture obtained from step (c) at about 120- 125°C for 1 to 4 hrs at pH between 10 and 12. e) concentrating the aqueous solution obtained in step (d), dehydration using organic solvents, and refluxing the concentrated gummy material with methanol to yield on cooling a powder of iron sucrose complex.

Further aspect of the present invention is the treatment of the ferric acetate with sucrose in situ in the presence of a base in aqueous medium to obtain iron sucrose complex.

Yet another aspect of the present invention is the treatment of ferric acetate with sucrose in aqueous base solution to release ferric hydroxide in situ and the said ferric hydroxide immediately forming highly stable iron sucrose complex. Still another aspect of the invention is addition of organic solvent, preferably, water miscible solvent to the reaction mixture containing iron sucrose complex to precipitate out iron sucrose complex.

Another aspect of the present invention is that the iron sucrose complex obtained complies with the Pharmacopoeial specifications (USP) permissible limit of turbidity.

Yet another aspect of the present invention is to provide simple and industrially viable process for the preparation of iron sucrose complex.

Still another aspect of the present invention is to provide reproducible process for the preparation of iron sucrose complex with high yield.

Further aspect of the present invention provides a new reproducible method for the preparation of iron sucrose complex using ferric acetate that is prepared freshly from ferric hydroxide. This method affords iron sucrose complex which is suitable for manufacture of injections complying with USP.

Another aspect the present invention provides a process for the preparation of iron sucrose complex in powder form.

DETAILED DESCRIPTION OF PRESENT INVENTION:

According to this invention a novel process for the preparation Iron sucrose complex, an aqueous solution of ferric chloride was filtered through hyflo and the said reaction mixture is cooled to 10-40⁰C with constant stirring. To this reaction mixture sodium carbonate solution was added slowly and the pH was adjusted to 4.0-6.0 and the reaction mixture is stirred constantly for 30 minutes. The ferric hydroxide slurry obtained from the reaction was diluted with water under stirring and allowed to settle for 1hr. The clear supernatant liquid is siphoned out and the slurry is filtered using Nutsch filter. The ferric hydroxide cake thus obtained is used as such for next step.

To get an aqueous solution of ferric acetate, the cake of ferric hydroxide was suspended in water and glacial acetic acid was added slowly with constant stirring for 45 minutes at 10° to 30⁰C until a clear solution is observed and thus a the clear dark brown solution of ferric acetate was obtained.

Ferric acetate solution was slowly mixed with sucrose with constant stirring and the pH of the reaction mixture is adjusted to 10.0 to 11.0 using sodium hydroxide solution with stirring. The mixture was stirred vigorously at 85- 90⁰C for 4 hrs. An aliquot sample of the reaction mixture was collected at different intervals until the GPC analysis complies with the weight average molecular weight of the product iron sucrose complex between 35000 - 55000 Daltons. The pH of the solution was further adjusted to10.5-11.5 using sodium hydroxide and the solution was autoclaved for 2.5 hrs.

The reaction mixture was concentrated under vacuum and an organic solvent such as methanol was added to the gummy material under stirring. The^' mixture was then heated under reflux for 1 hr with constant stirring. The mixture was cooled to room temperature to yield iron sucrose complex as powder which complies with USP.

Preparation of ferric hydroxide from ferric salt in water medium was effected by addition of inorganic base at a pH between 3.5 and 7.0 preferably between 4.0 and 6.0.

Temperature for the preparation of ferric hydroxide was maintained between 10° and 40⁰C preferably between 15°and 30°.

The iron compounds, used for making iron sucrose complex is ferric hydroxide or ferric acetate prepared by a specific methods described herein starting from ferric chloride, ferric bromide, ferric acetate or any other water soluble ferric salts. The inorganic bases used are sodium carbonate, potassium carbonate and sodium hydroxide preferably sodium carbonate.

Temperature for the preparation of ferric acetate from ferric hydroxide was maintained between 10° and 40° preferably between 15° and 30⁰C.

Sucrose was added into aqueous solution of ferric acetate or ferric hydroxide obtained in step (a) at 15°-40°C preferably at 15°-30°C with the molar ratio of sucrose to iron salts between 3.5 and 15. The pH of the reaction mixture adjusted between 9.5 and 12 preferably 10.0-11 using inorganic base.polymerisation is effected at 80-100⁰C preferably 85-90°.

The inorganic base used during polymerization are sodium hydroxide or potassium hydroxide preferably sodium hydroxide.

The aqueous iron sucrose solution was autoclaved between 120 and 125⁰C at pH between 10 and 12, preferably, 11.0 to 11.5.

The aqueous iron sucrose solution was autoclaved between 120 and 125°C for 1 to 4 hrs, preferably, 1.5 to 2.5 hrs.

It is pertinent to mention that by the above step the iron sucrose complex obtained complies with the test for turbidity as per USP.

Iron sucrose complex was isolated by concentration of the aqueous solution and dehydration using solvents like ethanol, acetone, methanol, isopropyl alcohol, t- butanol, preferably, methanol. The above step is carried out at selected temperature range between 60° and 80⁰C preferably between 60° and 70⁰C. Iron sucrose complex was obtained in a powder form by refluxing the concentrated gummy material with methanol and filtering the powder after cooling.

Accordingly, a process of preparing iron sucrose complex comprising steps of:

a) treating aqueous solution of ferric salt with a base to obtain ferric hydroxide wherein the pH is between 3.5 and 7.0 and temperature is between 10° and 40⁰C, b) preparing ferric acetate from ferric hydroxide obtained in step (a) by treatment with acetic acid at a temperature between10° and 40°, c) treating sucrose with aqueous solution of ferric acetate or ferric hydroxide obtained in step (a) at 15°-40°C with the molar ratio of sucrose to ferric compound between 3.5 and 15 and the pH of the reaction mixture adjusted to between 9.5 and 12 using inorganic base followed by polymerization at 80-100⁰C, d) autoclaving the reaction mixture obtained from step (c) at about 120- 125°C for 1 to 4 hrs at pH between 10 and 12, e) concentrating the aqueous solution obtained in step (d) .dehydration using organic solvents, and refluxing the concentrated gummy material with methanol to yield on cooling a powder of iron sucrose complex.

A process of preparing iron sucrose complex wherein the treatment of ferric acetate with aqueous base in presence of sucrose releases ferric hydroxide in situ in step c facilitating the formation of highly stable iron sucrose complex.

The molar ratio of sucrose to ferric acetate or ferric hydroxide is between 3.5 and 15. The pH in step (a) is adjusted to 3.5 and 7.0, preferably between 4.0 and 6.0, most preferably between 4.0 and 4.5. The temperature in step (a) and (b) is between 10⁰C and 40⁰C₁ preferably between 15° and 30⁰C₁ most preferably between 15° and 20⁰C. The pH in step (c) is adjusted to 9.5 and 12.0, preferably between 10.0 and 11.0, most preferably between 10.5 and 10.8. The temperature in step (d) selected between 80° and 100⁰C, preferably between 85° and 95°C, most preferably between 85° and 90⁰C.

The duration of autoclave in step (d) is at about 120-125⁰C for 1 to 4 hrs at pH between 10 and 12, preferably between 1hr and 2 hr, most preferably between 45 minutes and 1 hr.

The organic solvent or mixture of organic solvents is water miscible solvents wherein the said solvent is methanol, ethanol, isopropanol, t-butanol or mixture thereof, preferably ethanol and methanol, most preferably methanol.

Example I STEP I: PREPARATION OF FERRIC HYDROXIDE

A solution of ferric chloride (anhydrous) (1.0Kg) in distilled water (10L) was filtered through hyflo and cooled to 10-30⁰C under stirring. Sodium carbonate (30%) was added slowly and the pH was adjusted to 4.0-6.0. After the addition, stir for additional 30 minutes. The obtained ferric hydroxide slurry was diluted with distilled water under stirring and allowed to settle for 1hr. The clear supernatant liquid is siphoned out and the slurry is filtered using Nutsch filter. The ferric hydroxide cake thus obtained is used as such for next step.

STEP II: PREPARATION OF FERRIC ACETATE

Ferric hydroxide cake was suspended in water. Glacial acetic acid was added slowly with stirring at 10° to 40⁰C until a clear solution is observed. After addition, stir the mixture for 45 minutes. The clear dark brown solution of ferric acetate was used as such for next step. STEP III: POLYMERISATION

To ferric acetate solution from step No Il sucrose was added slowly with stirring. The pH was adjusted to 10.0 to 11.0 using sodium hydroxide solution with stirring. The mixture was stirred vigorously at 85-90⁰C for 4 hrs under nitrogen atmosphere.

The pH of the solution was further adjusted to 10.5-11.5 using sodium hydroxide and the solution was autoclaved for 2.5 hrs at 120-125⁰C.

STEP IV: ISOLATION OF IRON SUCROSE COMPLEX

The aqueous solution was concentrated under vacuum and methanol was added to the gummy material under stirring The mixture was heated under reflux for 1 hr with stirring, cooled to room temperature and the solid formed was filtered and dried under vacuum to yield Iron sucrose complex as powder complying with USP. Yield: 4 kg

Example Il

POLYMERISATION

Ferric hydroxide obtained from Step I in Example I was suspended in water. Sucrose was added slowly with stirring under nitrogen atmosphere. The pH was adjusted 10.0 to 11.0 using sodium hydroxide solution under stirring. The mixture was stirred vigorously at 85-9O⁰C for 4 hrs.

The solution was adjusted to pH 10.5-11.5 using sodium hydroxide and the solution was autoclaved for 2.5 hrs. Iron sucrose complex was isolated as per the procedure given in Example I. The above is illustrative of the present invention and is not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein.

Claims

We CLAIM:

1. A process of preparing iron sucrose complex comprising steps of:

(a) treating aqueous solution of ferric salt with a base to obtain ferric hydroxide wherein the pH is between 3.5 and 7.0 and temperature is between 1O⁰C and 40⁰C;

(b) preparing ferric acetate from ferric hydroxide that obtained in step (a) treated with acetic acid at a temperature 10° C and 40⁰C;

(c) treating a mixture of sucrose and ferric acetate obtained in step (b) or ferric hydroxide obtained in step (a) with base at15°C- 40⁰C and the pH adjust to 9.5 to12 followed by polymerization at 80-100°C;

(d) autoclaving the reaction mixture obtained from step (c) at about 120- 125⁰C for 1 to 4 hrs at pH between 10 and 12;

(e) concentrating of the aqueous solution obtained in step (c) and dehydrating using organic solvent or mixture of organic solvents at a temperature between 60° and 80⁰C;

(f) refluxing the material obtained in step (d) with methanol and filtering the mixture after cooling to obtain a powder of iron sucrose complex.

2. A process of preparing iron sucrose complex as claimed in claim 1, wherein the treatment of ferric acetate with aqueous base in presence of sucrose in step (c) releasing ferric hydroxide in situ facilitates the formation of highly stable iron sucrose complex.

3. A process of preparing iron sucrose complex as claimed in claim 1 , wherein the molar ratio of sucrose to ferric acetate is between 3.5 and 15.

4. A process of preparing iron sucrose complex as claimed in claim 1 , wherein the pH in step (a) is adjusted to 3.5 and 7.0, preferably between 4.0 and 6.0, most preferably between 4.0 and 4.5.

5. A process of preparing iron sucrose complex as claimed in claim 1.Wherein the temperature in step (a) & (b) is between 10⁰C and 40⁰C, preferably between 15° and 30°C, most preferably between 15° and 20⁰C.

6. A process of preparing iron sucrose complex as claimed in claim 1, wherein the pH in step (c) is adjusted to 9.5 and 12.0, preferably between 10.0 and 11.5, most preferably between 10.5 and 11.0.

7. A process of preparing iron sucrose complex as claimed in claim 1 , Wherein the temperature in step (c) selected between 80° and 100°C, preferably between 85° and 95°C, most preferably between 85° and 90°C.

8. A process of preparing iron sucrose complex as claimed in claim 1 , wherein the duration of autoclaving in step (d) is between 1 hr and 4 hrs, preferably between 1hr and 2 hr, most preferably between 45 minutes and 1 hr at 120- 125°C and the pH is between 10 and 12, preferably between 11 and 11.5, most preferably between 10.5and 11.0.

9. A process of preparing iron sucrose complex as claimed in claim 1 , wherein the organic solvent or mixture of organic solvents used is water miscible solvents such as methanol, ethanol, isopropanol, t-butanol or mixture thereof, preferably ethanol and methanol, most preferably methanol.

10. A process of preparing iron sucrose complex such as herein described and exemplified.