Title of Invention

NOVEL PROCESS FOR THE PREPARATION OF IRON SUCROSE COMPLEX

Abstract

A process of preparing iron sucrose complex comprising, (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°Cand40°C (b) preparing ferric acetate from ferric hydroxide that obtained in step (a) treated with acetic acid at a temperature 10° C and 40°C (c) treating sucrose with aqueous solution of ferric acetate obtained in step (b) at 15°C- 40X in the presence of a base and the pH of the reaction mixture adjusted to between 9.5 and 12 and the polymerisation is effected at 80-100°C wherein the reaction mixture was autoclaved for 1 to 4 hrs (d) concentrating the aqueous solution obtained in step (c) and precipitating using organic solvent or mixture of organic solvents at a temperature between 60° and 80°C (e) refluxing the precipitate obtained in step (d) with methanol and filtering mixture after cooling to obtain a powder of iron sucrose complex.

Full Text

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 favorable properties for therapeutic use, are of great interest, iron complexes with Dextran, Dextrose, maltose, Sucrose, Fructose are some of important complexes. Preparation of iron sucrose complex having molecular weight between 34000 and 60000 Daltons, and structural formula [Na2Fe5O8 (OH).3(H20)] n. m (C12H22O11) is an important therapeutic complex widely used to treat anemic. Preparation complexes of carbohydrates with metallic compounds were disclosed in many patents and publications. 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 -60°C and isolating the complex by precipitating with methanol or acetone. US 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) disclose a method for preparing iron-sugar complex .This method involves preparation of complex of calcium with sugar. The calcium sucrose complex was further treated with ferrous ammonium sulfate and maleic acid to yield an iron-sugar complex. The multistep process is tedious and is not convenient for the preparation of the complex in commercial quantities. T. Ramesh baburao, in IN 187116(2002) discloses 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. US Patent 2005/020987 discloses a process for the preparation of iron sucrose complex by heating the aqueous solution of sucrose with ferric hydroxide at 100 -105°C. WO 2005/000210 discloses a method for the preparation of Iron sucrose complex by mixing ferric chloride and sucrose followed by the addition of sodium hydroxide solution to give ferric hydroxide sucrose complex. The disadvantage of this method is the formed iron sucrose complex may have lot of unreacted 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 90-95°C. Therefore 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. Summary: Accordingly, one aspect of the present invention, a novel process for the preparation of iron sucrose complex comprising: a) treating aqueous solution of ferric salt with a base to obtain ferric hydroxide wherein the pH between 3.5 and 7.0 and temperature is between between 10° and 40°C. b) preparing ferric acetate from ferric hydroxide that obtained in step (a) treated with acetic acid at a temperature 10° and 40°. c) adding sucrose into aqueous solution of ferric acetate at 15°-40°C with the molar ratio between 3.5 and 15 and the pH of the reaction mixture adjusted to between 9.5 and 12 using inorganic base and the polymerisation is effected at 80-100°C. The aqueous iron sucrose solution was autoclaved for 1 to 4 hrs. d) concentrating the aqueous solution obtained in step (c) and precipitating using organic solvents at a temperature between 60° and 80°C. e) refluxing the concentrated gummy material with methanol and filtering mixture after cooling to obtain a powder of iron sucrose complex. Further aspect of the present invention, the ferric acetate treated with sucrose in situ in the presence of a base in aqueous medium to obtain iron sucrose complex. Yet another object of the present invention, the treatment of ferric acetate with sucrose in aqueous base solution release ferric hydroxide in situ and the said ferric hydroxide immediately form iron sucrose complex having highly stable. Still another aspect of the invention, adding organic solvent, preferably water miscible solvent into the reaction mixture containing iron sucrose complex to precipitate out iron sucrose complex. Another aspect of the present invention, the iron sucrose complex that complies permissible limit of turbidity as per pharmacopoeial specification. 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 having high yield. 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 in a powder form and an injectable form it complies with USP monograph. 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 25-30°C 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 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. To get an aqueous solution of ferric hydroxide, the cake of ferric hydroxide was suspended in distilled water and mixed thoroughly. Glacial acetic acid was added slowly with constant stirring for 45 minutes at 25° to 30°C until a clear solution is observed. The clear dark brown solution of ferric acetate was obtained. Ferric acetate solution is slowly mixed with sucrose with constant stirring under nitrogen atmosphere. 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 85-90°C for 4 hrs under nitrogen atmosphere. An aliquot sample was collected from reaction mixture of the reaction mixture at different intervals until the GPC analysis complied with the weight average molecular weight of the product iron sucrose complex between 45000 -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 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 and the solid formed was filtered using Nutsch filter. The material was dried under vacuum yield Iron sucrose complex that complies with pharmacopoeia specification. Preparation of ferric hydroxide from ferric salt in water by the addition of inorganic base at a pH between 3.5 and 7.0 preferably between 4.0 and 6.0. Temperature used for the preparation of ferric hydroxide between 10° and 40°C preferably between 25°and 30°. The ferric salts are ferric chloride, ferric bromide, ferric acetate, and ferric sulfate etc preferably ferric chloride and ferric acetate. The inorganic bases are sodium carbonate, potassium carbonate and sodium hydroxide preferably sodium carbonate. Temperature used for the preparation of ferric acetate form ferric hydroxide at a temperature between 10° and 40° preferably between 25° and 30°C. Ferric acetate solution is slowly mixed with sucrose with constant stirring under nitrogen atmosphere. 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 85-90°C for 4 hrs under nitrogen atmosphere. An aliquot sample was collected from reaction mixture of the reaction mixture at different intervals until the GPC analysis complied with the weight average molecular weight of the product iron sucrose complex between 45000 -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 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 and the solid formed was filtered using Nutsch filter. The material was dried under vacuum yield Iron sucrose complex that complies with pharmacopoeia specification. Preparation of ferric hydroxide from ferric salt in water by the addition of inorganic base at a pH between 3.5 and 7.0 preferably between 4.0 and 6.0. Temperature used for the preparation of ferric hydroxide between 10° and 40X preferably between 25°and 30°. The ferric salts are ferric chloride, ferric bromide, ferric acetate, and ferric sulfate etc preferably ferric chloride and ferric acetate. The inorganic bases are sodium carbonate, potassium carbonate and sodium hydroxide preferably sodium carbonate. Temperature used for the preparation of ferric acetate form ferric hydroxide at a temperature between 10° and 40° preferably between 25° and 30°C. Sucrose was added into aqueous solution of ferric acetate at 15°-40°C preferably at 25°-30°C with the molar radio 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 80-100°C 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 for 1 to 4 hrs, preferably, 1.5 to 2.5 hrs. It is pertinent to mention that by the above step the obtained iron sucrose complex complies with the test for turbidity as per pharmacopoeial specification. Iron sucrose complex was isolated by concentration of the aqueous solution and precipitating using solvents like ethanol, acetone, methanol, isopropyl alcohol, t-butanol. preferably, methanol. The above step is carried out a selected temperature between 60° and BOX preferably between 60° and 70°C. Iron sucrose complex was obtained in a powder form by refluxing the concentrated gummy material with methanol and filtering mixture after cooling. Accordingly, a process of preparing iron sucrose complex comprising;, (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°C and 40°C (b) preparing ferric acetate from, ferric hydroxide that obtained in step (a) treated with acetic acid at a temperature 10° C and 40°C (c) treating sucrose with aqueous solution of ferric acetate obtained in step (b) at 15°C- 40°C in the presence of a base and the pH of the reaction mixture adjusted to between 9.5 and 12 and the polymerisation is effected at 80-100°C wherein the reaction nnixture was autoclaved for 1 to 4 hrs (d) concentrating the aqueous solution obtained in step (c) and precipitating using organic solvent or mixture of organic solvents at a temperature between 60° and 80°C (e) refluxing the precipitate obtained in step (d) with methanol and filtering mixture after cooling to obtain a powder of iron sucrose complex. A process of preparing iron sucrose complex wherein the treatment of ferric acetate with sucrose in step (c) in aqueous base solution release ferric hydroxide in situ and the said ferric hydroxide immediately form iron sucrose complex having highly stable. The molar ratio of ferric acetate and sucrose 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 (b) is between 10°C and 40°C, preferably between 15° and 30°C, most preferably between 20° and 25°C. 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 100°C, preferably between 85° and 95°C, most preferably between 85° and 90°C. The duration of autoclave in step (c) is between 1 hr and 4 hrs, preferably between Ihr 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 25-30°C under stirring. Sodium carbonate (30%) was added slowly and the pH was adjusted to 4.0-6.0. After 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 Suspend the ferric hydroxide cake in distilled water. Glacial acetic acid was added slowly with stirring at 25° to 30°C 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 Ferric acetate solution from step No II and sucrose (3.0M) was added slowly with stirring under nitrogen atmosphere. The pH is adjusted to 10.0 to 11.0 using sodium hydroxide solution with stirring. The mixture was stirred vigorously at 85-90°C for 4 hrs under nitrogen atoosphere.An aliquot sample was collected from reaction mixture of the reaction mixture at different intervals until the GPC analysis complied with the weight average molecular weight of the product iron sucrose complex between 45000 -55000 Daltons . 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. 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 heated under reflux for 1 hr with stirring. Cool the mixture to room temperature and the solid formed was filtered using Nutsch filter and the. material was dried under vacuum yield Iron sucrose complex that complies with pharmacopoeia specification. Yield: 4 kg. Example II POLYMERISATION Ferric hydroxide obtained from Step I in Example I was suspended in water. Sucrose (3.0M) 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 85-90°C for 4 hrs under nitrogen atmosphere. An aliquot sample were collected from reaction mixture at different intervals until the GPC analysis to confirmed the required weight average molecular weight of iron sucrose complex (45000 -55000) Daltons. The pH of the solution was adjusted to10.5-11.5 using sodium hydroxide and the solution was autoclaved for 2.5 hrs. Isolate the iron sucrose complex same as per the procedure in Stage IV in Example 1, The foregoing 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. We CLAIM: 1. A process of preparing iron sucrose complex comprising, (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°Cand40°C (b) preparing ferric acetate from ferric hydroxide that obtained in step (a) treated with acetic acid at a temperature 10° C and 40°C (c) treating sucrose with aqueous solution of ferric acetate obtained in step (b) at 15°C- 40X in the presence of a base and the pH of the reaction mixture adjusted to between 9.5 and 12 and the polymerisation is effected at 80-100°C wherein the reaction mixture was autoclaved for 1 to 4 hrs (d) concentrating the aqueous solution obtained in step (c) and precipitating using organic solvent or mixture of organic solvents at a temperature between 60° and 80°C (e) refluxing the precipitate obtained in step (d) with methanol and filtering mixture after cooling to obtain a powder of iron sucrose complex. 2. A process of preparing iron sucrose complex as claimed in claim 1, the treatment of ferric acetate with sucrose in step (c) in aqueous base solution release ferric hydroxide in situ and the said ferric hydroxide immediately form iron sucrose complex having highly stable. 3. A process of preparing iron sucrose complex as claimed in claim 1, the molar ratio of ferric acetate and sucrose is between 3.5 and 15. 4. A process of preparing iron sucrose complex as claimed in claim 1, 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, the temperature in step (b) is between 10°C and 40°C, preferably between 15° and 30°C, most preferably between 20° and 25°C. 6. A process of preparing iron sucrose complex as claimed in claim 1, 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. 7. A process of preparing iron sucrose complex as claimed in claim 1, the temperature in step (d) 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 autoclave in step (c) between 1 hr and 4 hrs, preferably between 1hr and 2 hr, most preferably between 45 minutes and 1 hr. 9. A process of preparing iron sucrose complex as claimed in claim 1, wherein the organic solvent or mixture of organic solvents 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.

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