Title of Invention	AN IMPROVED MANUFACTURING PROCESS OF IRON SUCROSE
Abstract	The present invention involves the manufacturing process of iron sucrose complexes. Iron sucrose is basically from the haemitinic therapeutic group. It is a complex between polynuclear iron (Fe+3) hydroxide in a sucrose molecule. The molecular weight of the iron sucrose complex is ranging from 34,000 to 60,000 Daltons. Iron therapy is necessary in the treatment of iron deficiency anemia. Iron sucrose complex is prepared by reacting ferric hydroxide with sucrose molecules in basic condition. Therapeutically active iron-containing compositions comprising iron in a form capable of increasing amount of hemoglobin in the blood. Intravenous is particularly employed for patients, who cannot tolerate oral iron therapy, are unable to adequately absorb dietary iron, or who suffer hematopoietic failure. The iron sucrose complex is free of substantial free of excipients. The main object of the present invention is to provide the simplest and cost effective method for the production of iron sucrose complexes.

Title of Invention

AN IMPROVED MANUFACTURING PROCESS OF IRON SUCROSE

Abstract

The present invention involves the manufacturing process of iron sucrose complexes. Iron sucrose is basically from the haemitinic therapeutic group. It is a complex between polynuclear iron (Fe+3) hydroxide in a sucrose molecule. The molecular weight of the iron sucrose complex is ranging from 34,000 to 60,000 Daltons. Iron therapy is necessary in the treatment of iron deficiency anemia. Iron sucrose complex is prepared by reacting ferric hydroxide with sucrose molecules in basic condition. Therapeutically active iron-containing compositions comprising iron in a form capable of increasing amount of hemoglobin in the blood. Intravenous is particularly employed for patients, who cannot tolerate oral iron therapy, are unable to adequately absorb dietary iron, or who suffer hematopoietic failure. The iron sucrose complex is free of substantial free of excipients. The main object of the present invention is to provide the simplest and cost effective method for the production of iron sucrose complexes.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION [See section 10 and rule 13] Title: AN IMPROVED MANUFACTURING PROCESS OF IRON SUCROSE Applicant: Claris Lifesciences Limited, Claris Corporate Headquarters, Nr.Parimal Crossing, Ellisbridge, Ahmedabad - 380 006, Gujarat, India. The following specification particularly describes the invention and the manner in which it is to be performed. 1) TITLE OF INVENTION : AN IMPROVED MANUFACTURING PROCESS OF IRON SUCROSE 2) FIELD OF INVENTION [0001] The present invention relates to an improved manufacturing process of iron sucrose. 3) BACKGROUND OF THE INVENTION [0002] A. Intravenous Iron Therapy [0003] Iron therapy is necessary to replenish total body iron stores in patients with iron deficiency anemia. Therapeutically active iron-containing compositions comprise iron in a form capable of increasing the amount of hemoglobin in the blood. Intravenous (IV) is particularly employed for patients, who cannot tolerate oral iron therapy, are unable to adequately absorb dietary iron, or who suffer hematopoietic failure. [0004] B. Potential Side Effects of IV Iron Therapy [0005] One iron formulation, iron dextran, has been associated with significant adverse effects. Such effects are reported in approximately 26% of patients receiving iron dextran. See, Gupta et al., Kidney Int., 1999 May; 55(5): 1891-8. In this article they had given a data for iron dextrin while we are producing iron sucrose. [0006] Iron sucrose complex is one of the dextran free product. Product safety reports for iron sucrose demonstrate a low incidence of adverse effects. One study of 77 patients receiving a total of 757 doses, reported only 4 patients experiencing adverse events related to the administration of iron sucrose. The events reported were diarrhea, abdominal pain, nausea, constipation, and a transient minty taste. Ten patients in this study had a documented history of sensitivity reactions to iron dextran that were consistent with anaphylaxis and none experienced a hypersensitivity reaction with iron sucrose. See, Charytan et al., Am J Kidney Dis. 2001 February; 37(2): 300-7. [0007] C. Purity of Iron Sucrose Complexes [0008] Iron sucrose complex generally contains contaminants including excipients, free sucrose and by-products of the synthesis of the complex, which are readily detected by techniques such as H.P.L.C. The compendial method of analysis for Iron sucrose complex in sucrose is reported in United States Pharmacopoeia. The other tests like iron cotent, sucrose content, chloride content, arsenic content, turbidity test, molecular weight test etc. was also carried out to check the purity of iron sucrose complexes. [0009] A composition of iron sucrose complex comprising a narrower molecular weight distribution may yield a safer and more efficacious therapy. There exists a need for an iron sucrose complex preparative method that results in a product with low coast, narrower molecular weight and distribution as compared to existing compositions. 4( SUMMARY OF THE INVENTION [0010] According to one embodiment of the invention there is provided a process of preparing iron sucrose complex, substantially free of excipients, comprising the steps of: [0011] (a) reacting ferric chloride with sodium hydroxide to get ferric hydroxide which was reacted with the sucrose in an aqueous reaction mixture comprising sodium ions and hydrochloric acid, at a selected molar ratio of sucrose to ferric hydroxide, for a selected time interval, at a selected temperature and at a pH in the range from about 8.0 ±0.1; and [0012] Isolating iron sucrose complex from the aqueous reaction mixture. [0013] The selected molar ratio of sucrose to ferric iron is from about 13.50 to 16.50. [0014] The pH of the aqueous reaction mixture is in the range from about 5 to 11.5, preferably from about 10.5 to 11.5. [0015] The selected temperature of the aqueous reaction mixture is a temperature in the range from about 30 degree C to about 103 degree C, preferably in the range from about 100 degree C to about 103 degree C. The selected time interval is in the range from about 15 minutes to about 4 hours. [0016] According to one embodiments of the invention, the average molecular weight of the isolated iron sucrose complex is in the range from about 34,000 to about 60,000 Daltons, According to certain sub-embodiments of the invention, the weight average molecular weight of the prepared iron sucrose complex is about 34,000, about 40,000, about 45,000, about 50,000, about 55,000, about 60,000 Daltons. [0017] According to one embodiment of the invention, the step of isolating the iron sucrose comprises concentrating the reaction mixture to form a residue comprising iron sucrose complex. [0018] According to another embodiment of the invention, the step of isolating the iron sucrose complex comprises of various steps which can be describe as follows: [0019] (i) forming a mixture by adding to the reaction mixture for at least one water-miscible organic solvent in an amount sufficient to precipitate iron sucrose complex; and [0020] (ii) collecting the precipitated iron sucrose complex, from the mixture formed in step 19 (i). [0021] According to one embodiment of step of isolating the iron sucrose complex, the step of collecting the precipitated iron sucrose complex comprises filtration of the mixture formed in step 20 (ii). [0022] According to another embodiment of isolating the iron sucrose complex, the step of collecting the precipitated iron sucrose complex comprises centrifugation of the mixture formed in step 20 (ii). [0023] According to another embodiment of isolating the iron sucrose complex, the step of collecting the precipitated iron sucrose complex comprises drying of the mixture formed in step 20 (i). [0024] According to one preferred embodiment of the invention, the ferric hydroxide used to form the iron sucrose complex according to the invention is prepared by reacting at least one ferric salt, preferably, ferric chloride, ferric nitrate, or a mixture thereof, with at least one base in a reaction mixture comprising an aqueous medium. [0025] The collected iron sucrose complex is optionally purified, such as by. [0026] (a) dissolving the isolated iron sucrose complex in an aqueous solvent; [0027] (b) forming a mixture by adding to the solution of iron sucrose complex at least one water-miscible organic solvent in an amount sufficient to precipitate iron sucrose complex from the solution. [0028] (c) separating the purified iron sucrose complex from the mixture formed in step 27 (b). [0029] According to one embodiment of purification of the collected iron sucrose complex, the step of separating the purified precipitated iron sucrose complex comprises filtration of the mixture formed in step 27 (b). [0030] According to another embodiment of purification of the collected iron sucrose complex, the step of separating the purified precipitated iron sucrose complex comprises centrifugation of the mixture formed in step 27 (b). [0031] The purified iron sucrose complex is optionally dried. [0032] According to another embodiment of the invention there is provided a process of preparing an aqueous solution of Ferric hydroxide: [0033] (a) reacting ferric chloride and sodium carbonate in presence of water for injection comprising sodium ions, for a selected time interval, at a selected temperature, and at a pH in the range from about 8.0 + 0.1; [0034] The solution given in 33 (a) was stir for the selected time. [0035] The selected time interval as per the 33 (a) was 15 minutes. [0036] The selected temperature as per the 33 (a) was 30 degree C to 35 degree C. [0037] The product was taken under the process of centrifugation where it was wash with the water for injections to remove sodium slats for the selected time. [0038] A process according to 37 the sodium slats is sodium chloride. [0039] A process according to claim 37 the selected time is 15 hours. [0040] The Hydrolysis process was carried out by following steps: (a) the wet cake produce from claim 13 was taken in water for injection for selected time at room temperature; (b) in this solution the addition of sucrose was carried out with constant stirring; (c) the hydrochloric acid was added in this solution and stir for selected time; (d) add more hydrochloric acid to get the selected molarity level; (e) stir for 6 hours at temperature 30 to 35 °C; (f) add sodium hydroxide to get the pH between 5.25 to 5.35 and then stir at room temperature for 10 minutes. [0041] A process according to 40 (a) the selected time is 30 minutes. [0042] A process according to 40 (c) the selected time is 15 minutes. [0043] A process according to 40 (d) the selected molarity level is 1.65 to 1.70. [0044] The product from claim 40 was taken for the process of centrifugation where it was wash with the water for injections to remove sodium slats for the selected time. [0045] A process according to 44 the sodium slats is sodium chloride. [0046] A process according to 44 the selected time is 30 hours. [0047] The Complexation process was carried out by following steps: (a) with the help of sucrose and sodium hydroxide with the wet cake which was made by the claim 20 at the selected temperature, selected pH and the selected time; (b) the wet cake from claim 20 was dissolved in water for injection for 15 min; (c) sucrose solution was added in the solution made by 23 (a) in by adding the sodium hydroxide to adjust the pH between 11.0 to 11.50; (d) the solution was heated for the selected time and selected temperature; (e) check the molecular weight of the product produce from the claim 23 (d) after 4 hours; (f) cool the solution made up from the claim 23 (e) at selected temperature; (g) the solution made from claim 23 (f) was pass form the filter 0.2 filter cartridge; (g) the solution made from claim 23 (f) was adjusted for the pH between 11.00 to 11.50 by adding sodium hydroxide. [0048] The isolation was carried out with product made by 47 (f) was mixed with the organic solvents between 2 to 6 hours stirring. [0049] As per the process of 48, the organic solvents are Acetone, alcohol, Iso propyl alcohol. [0050] A product from 49 was centrifuge to remove the mixture of water for the injection and organic solvent. [0051] A centrifuge product was dry at selected temperature, for selected time and for selected pressure. [0052] A process claim in 51, the selected temperature is 80 °C. [0053] A process claim in 51, the selected time is 6 hours. [0054] A process claim in 51, the selected pressure is 0.2 mmHg vacuum. [0055] A Final product according to claim 52, wherein the iron sucrose complex contain from about 4.5 to 7 % ferric iron by weight. [0056] Preferably, the pharmaceutical composition of the invention comprises an iron sucrose complex prepared by the process according to the present invention. Definitions [0057] The term "excipients" as used herein refers to components of the product of a process of the invention that are other than iron sucrose complex. Examples include, free sucrose, water and solvents, and substances related to the synthesis process. By "substances related to the synthesis process" is meant the reagents used in the synthesis and products of degradation of either the synthesis reagents of the reaction products. [0058] The term "base" as employed herein refers to a chemical species that donates electrons or hydroxide ions (Arrhenius definition) or that accepts protons (Bronsted definition). Bases include strong bases, i.e., bases that are completely dissociated in aqueous solution and weak bases, i.e., bases that are only partially dissociated in aqueous solution. Examples of strong bases include sodium hydroxide and potassium hydroxide. Examples of weak bases include ammonia and alkyl amines. [0059] The expression "water-miscible organic solvent," unless otherwise indicated, refers to an organic solvent, which is soluble in water in all proportions at standard temperature and pressure. Suitable water-miscible organic solvents include, for example, methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, dioxane, dimethyl formamide, dime thy lace tamide, and N-methylpyrrolidinone. 5) DETAILED DESCRIPTION OF THE INVENTION [0060] The present invention provides a process for the preparation of iron sucrose complexes. The iron sucrose complexes can be used to formulate a therapeutic iron sucrose composition containing lower levels of contaminants. [0061] A. Ferric Chloride The ferric chloride can be used as different names like flores martis, iron chloride, Iron (III) choloride, Iron (III) chloride solution, iron sesquichloride, Iron trichloride. [0062] A. Ferric Hydroxide [0063] The term "ferric hydroxide" as employed herein, includes the various forms of ferric hydroxide, including, for example, hydrated ferric oxide, ferric oxy hydroxide, polymeric ferric hydroxide, ferric hydroxide gel, partially neutralized ferric salts and partially neutralized polymeric ferric salts. [0064] B. Preparation of Ferric Hydroxide [0065] The ferric hydroxide utilized as the starting material in the process of the present invention may be prepared by reacting a ferric salt with at least about one molar equivalent of a base, based on the amount of the ferric salt. A mixture of ferric salts, and/or a mixture of bases, may be employed. Suitable ferric salts include ferric salts wherein the anion is an anion of an acid such as, for example, chloride, bromide, iodide, nitrate, sulfate, acetate, citrate and other acid anions. Preferred ferric salts include, for example ferric chloride and ferric nitrate. [0066] Suitable bases for reaction with the ferric salt include, for example, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, water-soluble amines and mixtures thereof. Preferred bases include sodium carbonate, sodium bicarbonate, sodium hydroxide, tris-hydroxymethyl-aminoethane and mixtures thereof. [0067] The ferric hydroxide may be prepared by (a) providing a reaction mixture comprising a ferric salt dissolved in an aqueous medium; (b) adding to the reaction mixture a base with ferric salt in presence of water for injection; (c) allowing the reaction mixture to equilibrate for a time interval greater than about 15 minutes (d) collecting the ferric hydroxide from the reaction mixture. [0068] The base may be the same, or may be different bases. The base may be added to the reaction mixture in solution or suspension in an aqueous solvent. Alternately the bases may be added neat, i.e., a base such as sodium carbonate may be added as a dry solid. [0068] The base may be added to the reaction mixture batchwise, i.e., all at once, or continuously or semi-continuously over a time interval at a constant or variable addition rate. A slow continuous addition may be performed as a titration wherein the pH of the mixture is continuously monitored, preferably using a pH meter. The addition of the base may be stopped when a selected pH, preferably about 8.0 + 0.1 came. [0069] After the addition of the first base to the reaction mixture, the reaction mixture is allowed to equilibrate, with or without stirring. The temperature is preferably maintained in the range from about 30 degree to about 35 degree C. The pH of the reaction mixture is typically observed to drop to a pH in the range from about to about 8.0 + 0.1 during the time interval when the reaction mixture is allowed to equilibrate. [0070] Following complete addition of the base, the reaction mixture, comprising a suspension of ferric hydroxide, is allowed to equilibrate for a time interval from about 15 minutes. The ferric hydroxide precipitate is observed to settle during the equilibration period. [0071] The ferric hydroxide precipitate may be collected from the reaction mixture by any suitable method, including, for example, filtration, centrifugation, or decanting. Filtration is preferred. Suitable filtration methods include vacuum filtration, e.g., for example through a Buchner funnel. The resulting filter cake comprising ferric hydroxide is washed with water for injection. [0072] To prepare iron sucrose, a suspension or slurry of ferric hydroxide, as prepared above, is reacted with sucrose in a reaction mixture comprising sodium ions. The sucrose is preferably provided as a solution of sucrose in an aqueous solvent. The sodium ions are preferably provided by addition of a sodium base, preferably aqueous sodium hydroxide. The mixture of the ferric hydroxide and sucrose may become basic upon the addition of the sodium base. The sodium base may be added to the aqueous medium, and the ferric hydroxide may subsequently be added. Alternately, the sodium base may be added to the mixture of the ferric hydroxide and sucrose in the aqueous medium. [0073] The reaction mixture is optionally heated to a temperature in the range from about 30degree to about 35 degree C, prior to the step of isolating iron sucrose complex from the reaction mixture. [0074] The reaction of ferric hydroxide and sucrose may be optionally monitored to determine the weight average molecular weight and purity of the iron sucrose product. Removing an aliquot of the reaction mixture and conducting a molecular weight analysis on the aliquot was done for monitoring. [0075] When the reaction of ferric hydroxide and sucrose is complete (as determined by observation of the clarity of the reaction mixture) the iron sucrose complex is isolated from the reaction mixture. Isolation may be achieved by adding one or more water-miscible organic solvents to the reaction mixture to precipitate the iron sucrose complex. Suitable methods for collecting the product include, for example, filtration, centrifugation and decanting. The product is preferably collected by filtration. The selection of suitable filtration media, e.g., for example, a sintered glass funnel or Buchner funnel, is within the capability of one of ordinary skill in the art. [0076] Alternately, the iron sucrose complex is isolated from the reaction mixture by concentrating the reaction mixture to form a residue comprising the iron sucrose complex. Concentration of the reaction mixture may be carried out by centrifugation method. [0077] The centrifugation was last for about 30 hours, preferably it was 25 hours. [0078] The wet cake of product of iron and sucrose again react with again sucrose and sodium hydroxide. The reaction was carried out at 100 degree C to 103 degree C. the pH was 10.50 to 11.50. The time for reacting the compounds was 4 hours. [0079] The resulting complex was isolated with the organic solvents and the water for injection. [0080] The organic solvents group which may ranging from methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, dioxane, dimethyl formamide, dimethylacetamide, and N-methylpyrrolidinone. [0081] According to the invention, there is provided a pharmaceutical composition in solid dosage form comprising a pharmaceutically acceptable carrier and an iron sucrose complex having a molecular weight in the range from about 20,000 to about 400,000 Daltons. The pharmaceutical composition of the invention may be formulated for oral administration and may be in the form of a tablet, capsule, pill, powder, granule or other suitable solid dosage form with suitable excipients and additives. [0082] The pharmaceutical composition according the invention comprises an iron sucrose complex that contains from about 1 to about 33.33% ferric iron by weight. [0083] The practice of the invention is illustrated by the following examples. Example 1 Preparation of Iron Sucrose Complex [0084] To a solution of ferric chloride Anhydrous (12.6 gm) in WFI (200 ml) is added sodium carbonate (12.4 gm) solution in WFI (100 ml) with continue stirring and the pH was about 3.80. [0085] The colloidal ferric oxyhydroxide formed is washed several times with water to remove the chloride salt (check with silver nitrate solution). Then ferric oxyhydroxide is suspended in 500 ml of water and added 50 gm sucrose in 200 ml WFI at 25° C. [0086] The mixture is stirred about 5 minutes. Then the pH is brought to 10.5 by 10% NaOH solution. [0087] Then the reaction mixture is heated for 6 hrs. At 100°C. Cool the solution at 30°C and filter by 0.45µm filter paper. Example 2 Preparation of Iron Sucrose Complex [0088] To a solution of ferric chloride Anhydrous (12.6 gm) in WFI (200 ml) is added sodium carbonate (12.4 gm) solution in WFI (100 ml) with continue stirring (pH = 3.80). [0089] The colloidal ferric oxyhydroxide formed is washed several times with water to remove the chloride salt (check with silver nitrate solution). [0090] Then ferric oxyhydroxide is suspended in 500 ml of water and added 50 gm sucrose in 200 ml WFI at 25° C. [0091] The mixture is stirred about 5 minutes. Then the pH is brought to 10.5 by 10% NaOH solutions. [0092] Then the reaction mixture is heated for 6 hrs. At 100°C. Cool the solution at 30°C and filter by 0.45µm filter paper. [0093] After that pass solution in ultra filtration cassette. Then isolated by Acetone. Example 3 Preparation of Iron Sucrose Complex [0094] Step-I Preparation Of Ferric hydroxide: [0095] Clean 2 liter round bottom flask with water for injection and check conductivity (NMT2 .0 uS). Take 100 ml water for injection and to it add 12.6 gm Ferric chloride portion wise under constant stirring such that the temperature is maintained at 30 °C throughout the addition (Take care as exothermic reaction takes place). Take 45 ml water for injection and to it add 12.6 gm sodium carbonate slowly under constant stirring such that the temperature is maintained at 30 °C throughout the addition. Adjust pH of the Ferric Chloride solution by adding the sodium carbonate solution to 8.0 ±0.1 under constant stirring at less than 30 °C. Stir the above solution for 10 mins. Filter and was wash with WFI up to chloride removed. (Check by titration with 0.01 M silver nitrate in Filtrate). [0096] Step-II Hydrolysis [0097] Take wet cake in 250 mL WFI and Dissolve 50gm sucrose in 25 ml water for injection and add this solution to the solution obtained above under constant stirring. Adjust the Molarity of above solution to 1.2 to 2.0 with 8N Hydrochloric acid (Check by titrating against 0.1 M sodium hydroxide). Approx. 100 ml of 8N hydrochloric acid is required.. Clean 2.0-litre round bottom flask with water for injection and check conductivity (NMT 2 .0 uS). Stirring for 2 hours at room temp. ( 25 -30 ° C ). Adjust the pH of the reaction mass to 5.25 - 5.35 by 4N sodium hydroxide.. The crude product is obtained. Stir at room temp for 10 minutes. Filter it and wash with water for injection till the chloride is removed. (Check by titration with 0.01 M silver nitrate in Filtrate). Collect the wet cake for next step. [0098] Step-Ill Cornplexation: [0099] Dissolve the wet cake obtained in 40 ml water for injection and add sucrose solution (100 gm sucrose in 50 ml Water for injection) and adjust the pH to 11.5 by 4N sodium hydroxide. Start heating and maintain heating the above solution for 4 hrs at 100°C. Cool the solution to RT within 30 minutes. Filter through 0.2 micron filter membrane. And collect solution for isolation. [0100] Step- IV Isolation: [0101] Clean 20 -lit round bottom flask with water for injection and check conductivity (NMT 2.0 pS). Add 1.6-liter acetone and start stirring. Add the solution obtained in Step II drop wise within 6 hrs with constant stirring. Stir for 2 hrs after addition is complete. Stop the stirring. Filter the solution and wash with Fresh Acetone. Collect the Powder. [0102] Step-V Drying [0103] Clean the vacuum oven and check vacuum and temperature. Put the powder in tray and dry it at 80° C for 6 hrs. Final collect dry powder in plastic Jar. Example 4 Preparation of Iron Sucrose Complex [0104]Step-I Preparation Of Ferric hydroxide: Clean 5 liter round bottom flask with water for injection and check conductivity (NMT 2 .0 uS). Take 500 ml water for injection and to it add 100 gm Ferric chloride portion wise under constant stirring such that the temperature is maintained at 30 °C throughout the addition (Take care as exothermic reaction takes place). Take 450 mL water for injection and to it add 110 gm sodium carbonate slowly under constant stirring such that the temperature is maintained at 30 °C throughout the addition. Adjust pH of the Ferric Chloride solution by adding the sodium carbonate solution to 8.0 + 0.1 under constant stirring at less than 30 °C. Stir the above solution for 10 mins. Add 1.2 liter of WFI and stirring for 2 hrs at room temp. Filter and was wash with WFI up to chloride removed. (Check by titration with 0.01 M silver nitrate in Filtrate). [0105] Step-II Hydrolysis [0106] Clean 2.0-litre round bottom flask with water for injection and check conductivity (NMT 2 .0 uS) Take wet cake in 500 mL WFI and Dissolve 400gm sucrose in 200 ml water for injection and add this solution to the solution obtained above under constant stirring. Adjust the Molarity of above solution to 1.65 to 1.7 with 8N Hydrochloric acid (Check by titrating against 0.1 M sodium hydroxide). Approx. 300 ml of 8N hydrochloric acid is required.. Stirring for 2 hours at room temp. ( 25 -30 ° C ). Adjust the pH of the reaction mass to 5.25 - 5.35 by 4N sodium hydroxide.. The crude product is obtained. Stir at room temp for 10 minutes. Filter it and wash with water for injection till the chloride is removed. (Check by titration with 0.01 M silver nitrate in Filtrate). Collect the wet cake for next step. [0107] Step-Ill Complexation: [0108] Clean 2.0-litre round bottom flask with water for injection and check conductivity (NMT 2.0 uS). Dissolve the wet cake obtained in 300ml water for injection and add sucrose solution 200 gm sucrose in 100 ml Water for injection and adjust the pH to 11.5 by 4N sodium hydroxide. Start heating and maintain heating the above solution for 4 hrs at 100°C. Cool the solution to RT within 30 minutes. Filter through 0.2 micron filter membrane. And collect solution for isolation. [0109] Step- IV Isolation: [0110] Clean 20 -lit round bottom flask with water for injection and check conductivity (NMT 2.0 uS). Add 11-liter acetone and start stirring. Add the solution obtained in Step II drop wise within 6 hrs with constant stirring. Stir for 2 hrs after addition is complete. Stop the stirring. Filter the solution and wash with Fresh Acetone. Collect the Powder. [0111] Step-IV Drying [0112] Clean the vacuum oven and check vacuum and temperature. Put the powder in tray and dry it at 80° C for 6 hrs. Final collect dry powder in plastic Jar. Example 5 Preparation of Iron Sucrose Complex [0113] Step - I Preparation of ferric hydroxide [0114] Clean 50 liter RBF-1 with Water for injections and check conductivity (Not more than 2.0 uS at 25°C) [0115] Send the sample in QC for conductivity. After release from QC start further process. [0116] Take 5.0 Litres Water for injections and to it add 1.0 Kg Ferric chloride portion wise under constant stirring for 15 minutes after last portion addition of FeCl3 such that the temperature is maintained at between 30° and 35°C throughout the addition (Take care as exothermic reaction takes place). [0117] Take 4.5 Liters Water for injections and to it add 1.10 Kg sodium carbonate slowly under constant stirring such that the temperature is maintained at 30 °C throughout the addition. [0118] Adjust pH of the Ferric Chloride solution by adding the sodium carbonate solution to 8.0 + 0.1 under constant stirring at less than 30 °C. [0119] Note: Send the sample for pH analysis only after precipitation of Fe(OH)3 took place. Sample quantity shall not be more than 50 mL. [0120] Stir the above solution for 2 hrs. [0121] Centrifuge [0122] Clean Centrifuge with Water for injections and check conductivity (Not more than 2.0 pS at 25°C ) [0123] Send the sample in QC for conductivity. After release from QC, start further process. [0124] Centrifuge the above solution and wash with Water for injections at least for 15 hours. [0125] Continue the process till chloride is removed. [0126] Send the sample in QC after 15 hours for the chloride test. [0127] After QC release, start further process. [0128] Collect the wet cake for next step. [0129] STEP - II HYDROLYSIS [0130] Clean 50-litre RBF-1 with Water for injections and check conductivity (Not more than 2.0 uS at 25°C ) [0131] Send the sample in QC for conductivity. After release from QC start further process. [0132] Take wet cake from step - I and dissolve 5 liter WFI and stirring for 30 min at room temp. [0133] Add 3 Kg sucrose in this solution under constant stirring. [0134] Add approximately 2.5 liter 8N hydrochloric acid in the above slurry. [0135] Stir for 15 minutes [0136] Send the sample in QC for the analysis of Molarity of the above solution against 0.1 M sodium hydroxide. [0137] Molarity shall be between 1.65 and 1.75. If not add stepwise quantity of 8N Hydrochloric acid & repeat the process. [0138] Stirring for 6 hours at 30- 35° C. [0139] After 6 hrs stirring Adjust the pH of the reaction mass to 5.25 -5.35 by 4N sodium hydroxide. An approx. 4.0 to 4.5 liter of sodium hydroxide is consumed. [0140] The crude product is obtained. Stir at room temp for 10 minutes. [0141] CENTRIFUGE [0142] Clean Centrifuge with Water for injections and check conductivity (Not more than 2.0 uS at 25°C) [0143] Send the sample in QC for conductivity. After release from QC start further process. [0144] Centrifuge the above solution and wash with Water for injections at least for 30 hours. [0145] Continue the process till chloride is removed. [0146] Send the sample in QC after 25 hours for the chloride test. [0147] After QC release, start further process. [0148] Collect the wet cake for next step. [0149] STEP-III COMPLEXATION [0150] Clean 50-litre RBF-II with Water for injections and check conductivity (Not more than 2.0 uS at 25°C ) [0151] Send the sample in QC for conductivity. After release from QC start further process [0152] Dissolve the wet cake obtained from step - II in 3-liter water and stirring for 15 min. [0153] Add sucrose solution (2.5 kg sucrose in 1 liters Water for injections) and adjust the pH to 11.00 to 11.50 by 4N sodium hydroxide. [0154] Heat the above solution for 4 hrs at 100 - 103°C. [0155] During reflux check the pH of the solution every hours, pH shall be 10.5 to 11.0 during reflux. Adjust the pH if required by addition of 4N NaOH solution. [0156] Check the molecular weight after 4 hrs. [0157] Cool the solution upto 40°C to 50°C. [0158] Filter through 0.2 filter cartridge. After filtration check pH the solution. pH shall be 11.00 to 11.50 Adjust the pH if required by addition of 4N NaOH solution. [0159) Collect the solution for next step. [0160] STEP - IV ISOLATION [0161] Clean 200-Iit RBF-III with Water for injections and check conductivity (Not more than 2.0 pS at 25°C ) [0162] Send the sample in QC for conductivity. After release from QC start further process [0163] Add 110-liter acetone after filtration through 0.2 □ filter cartridge and start stirring. [0164] Add the solution obtained in Step III (Complexation solution) drop wise within 6 hrs with constant stirring. [0165] Stir for 2 hrs after addition is complete. [0166] Stop the stirring. [0167] CENTRIFUGE [0168] Clean Centrifuge with Water for injections and check conductivity (Not more than 2.0 pS at 25°C) [0169] Send the sample in QC for conductivity. After release from QC start further process. [0170] Centrifuge it and wash with 5.0 liter fresh acetone. [0171] Collect the wet cake for next step. [0172] Clean the vacuum oven and check vacuum and temperature. [0173] Put the powder in tray and dry it at 80° C for 6 hrs at 0.2 mm.Hg vacuum. 6. CLAIMS: What is claimed is: 1. A process of preparing crystalline iron sucrose complex of mol. Wt. 34000 to 60000 dalton & substantially free of excipients, comprising the steps of: (a) Preparation of ferric hydroxide from ferric salts in presence of water for injection at a selected ratio, time, pH and temperature, (b) Centrifugation of the ferric hydroxide for selected time, (c) Hydrolysis of the ferric hydroxide with sucrose in presence of the Hydrochloric acid and Sodium hydroxide to obtain solution, (d) Centrifugation of the solution at selected temperature for selected time with water for injection to obtain a cake, (e) Complexation of the wet cake with sugar and Sodium hydroxide at a selected temperature, selected time and selected pH, (f) Isolation of complex is carrying out with organic solvents at selected time and selected ratio, (g) Centrifuge the obtained product with the mixture of the water for injection and the organic solvents, (h) Drying of the complex is carry out at selected temperature, selected pressure and for selected time. 2. A process as claimed in claim 1 wherein the the ferric salt is ferric chloride. 3. A process as claimed in claim 1 wherein centrifugation of product carried out remove sodium salts. 4. A process as claimed in claim 1 wherein the hydrolysis is carried out by (a) The addition of sucrose to ferric hydroxide was carried out with constant stirring. (b) The hydrochloric acid was added to it, (c) Adding more hydrochloric acid to get the selected molarity level of 1.65 to 1.70 & Stir for 6 hours at temperature 30 to 35 0C; (d) Add sodium hydroxide to get the pH between 4.5 to 5.5 and then stir at room temperature for 10 minutes. 5. A process as claimed in claim 1 wherein the Complexation process was carried out by following steps: (a) sucrose and sodium hydroxide with the wet cake carried out by dissolving the wet cake in water. (c) Sucrose solution was added to it & adding the sodium hydroxide to adjust the pH between 11.0 to 11.50. (d) heated it for the selected time and selected temperature. (e) Check the molecular weight of the product, (f) Cooling the solution , (g) filtering the solution through the 0.2M filter cartridge. 6. A process as claimed in claim 1 wherein the isolation was carried out with water miscible organic solvent selected from acetone, alcohol and Iso propyl alcohol.

Full Text

FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
[See section 10 and rule 13]
Title: AN IMPROVED MANUFACTURING PROCESS OF
IRON SUCROSE
Applicant: Claris Lifesciences Limited,
Claris Corporate Headquarters, Nr.Parimal Crossing, Ellisbridge,
Ahmedabad - 380 006, Gujarat, India.

The following specification particularly describes the invention and the manner in which it is to be performed.

1) TITLE OF INVENTION :
AN IMPROVED MANUFACTURING PROCESS OF IRON SUCROSE
2) FIELD OF INVENTION
[0001] The present invention relates to an improved manufacturing process of iron sucrose.
3) BACKGROUND OF THE INVENTION
[0002] A. Intravenous Iron Therapy
[0003] Iron therapy is necessary to replenish total body iron stores in patients with iron deficiency anemia. Therapeutically active iron-containing compositions comprise iron in a form capable of increasing the amount of hemoglobin in the blood. Intravenous (IV) is particularly employed for patients, who cannot tolerate oral iron therapy, are unable to adequately absorb dietary iron, or who suffer hematopoietic failure.
[0004] B. Potential Side Effects of IV Iron Therapy
[0005] One iron formulation, iron dextran, has been associated with significant adverse effects. Such effects are reported in approximately 26% of patients receiving iron dextran. See, Gupta et al., Kidney Int., 1999 May; 55(5): 1891-8. In this article they had given a data for iron dextrin while we are producing iron sucrose.
[0006] Iron sucrose complex is one of the dextran free product. Product safety reports for iron sucrose demonstrate a low incidence of adverse effects. One study of 77 patients receiving a total of 757 doses, reported only 4 patients experiencing adverse events related to the administration of iron sucrose. The events reported were diarrhea, abdominal pain, nausea, constipation, and a transient minty taste. Ten patients in this study had a documented history of sensitivity reactions to iron dextran that were consistent with anaphylaxis and none experienced a hypersensitivity reaction with iron sucrose. See, Charytan et al., Am J Kidney Dis. 2001 February; 37(2): 300-7.
[0007] C. Purity of Iron Sucrose Complexes
[0008] Iron sucrose complex generally contains contaminants including excipients, free sucrose and by-products of the synthesis of the complex,

which are readily detected by techniques such as H.P.L.C. The compendial method of analysis for Iron sucrose complex in sucrose is reported in United States Pharmacopoeia. The other tests like iron cotent, sucrose content, chloride content, arsenic content, turbidity test, molecular weight test etc. was also carried out to check the purity of iron sucrose complexes.
[0009] A composition of iron sucrose complex comprising a narrower molecular weight distribution may yield a safer and more efficacious therapy. There exists a need for an iron sucrose complex preparative method that results in a product with low coast, narrower molecular weight and distribution as compared to existing compositions.
4( SUMMARY OF THE INVENTION
[0010] According to one embodiment of the invention there is provided a process of preparing iron sucrose complex, substantially free of excipients, comprising the steps of:
[0011] (a) reacting ferric chloride with sodium hydroxide to get ferric hydroxide which was reacted with the sucrose in an aqueous reaction mixture comprising sodium ions and hydrochloric acid, at a selected molar ratio of sucrose to ferric hydroxide, for a selected time interval, at a selected temperature and at a pH in the range from about 8.0 ±0.1; and
[0012] Isolating iron sucrose complex from the aqueous reaction mixture.
[0013] The selected molar ratio of sucrose to ferric iron is from about 13.50 to 16.50.
[0014] The pH of the aqueous reaction mixture is in the range from about 5 to 11.5, preferably from about 10.5 to 11.5.
[0015] The selected temperature of the aqueous reaction mixture is a temperature in the range from about 30 degree C to about 103 degree C, preferably in the range from about 100 degree C to about 103 degree C. The selected time interval is in the range from about 15 minutes to about 4 hours.
[0016] According to one embodiments of the invention, the average molecular weight of the isolated iron sucrose complex is in the range from about 34,000 to about 60,000 Daltons, According to certain sub-embodiments of the invention, the weight average molecular weight of

the prepared iron sucrose complex is about 34,000, about 40,000, about 45,000, about 50,000, about 55,000, about 60,000 Daltons.
[0017] According to one embodiment of the invention, the step of isolating the iron sucrose comprises concentrating the reaction mixture to form a residue comprising iron sucrose complex.
[0018] According to another embodiment of the invention, the step of isolating the iron sucrose complex comprises of various steps which can be describe as follows:
[0019] (i) forming a mixture by adding to the reaction mixture for at least one water-miscible organic solvent in an amount sufficient to precipitate iron sucrose complex; and
[0020] (ii) collecting the precipitated iron sucrose complex, from the mixture formed in step 19 (i).
[0021] According to one embodiment of step of isolating the iron sucrose complex, the step of collecting the precipitated iron sucrose complex comprises filtration of the mixture formed in step 20 (ii).
[0022] According to another embodiment of isolating the iron sucrose complex, the step of collecting the precipitated iron sucrose complex comprises centrifugation of the mixture formed in step 20 (ii).
[0023] According to another embodiment of isolating the iron sucrose complex, the step of collecting the precipitated iron sucrose complex comprises drying of the mixture formed in step 20 (i).
[0024] According to one preferred embodiment of the invention, the ferric hydroxide used to form the iron sucrose complex according to the invention is prepared by reacting at least one ferric salt, preferably, ferric chloride, ferric nitrate, or a mixture thereof, with at least one base in a reaction mixture comprising an aqueous medium.
[0025] The collected iron sucrose complex is optionally purified, such as by.
[0026] (a) dissolving the isolated iron sucrose complex in an aqueous solvent;
[0027] (b) forming a mixture by adding to the solution of iron sucrose

complex at least one water-miscible organic solvent in an amount sufficient to precipitate iron sucrose complex from the solution.
[0028] (c) separating the purified iron sucrose complex from the mixture formed in step 27 (b).
[0029] According to one embodiment of purification of the collected iron sucrose complex, the step of separating the purified precipitated iron sucrose complex comprises filtration of the mixture formed in step 27 (b).
[0030] According to another embodiment of purification of the collected iron sucrose complex, the step of separating the purified precipitated iron sucrose complex comprises centrifugation of the mixture formed in step 27 (b).
[0031] The purified iron sucrose complex is optionally dried.
[0032] According to another embodiment of the invention there is provided a process of preparing an aqueous solution of Ferric hydroxide: [0033] (a) reacting ferric chloride and sodium carbonate in presence of water for injection comprising sodium ions, for a selected time interval, at a selected temperature, and at a pH in the range from about 8.0 + 0.1;
[0034] The solution given in 33 (a) was stir for the selected time.
[0035] The selected time interval as per the 33 (a) was 15 minutes.
[0036] The selected temperature as per the 33 (a) was 30 degree C to 35 degree C.
[0037] The product was taken under the process of centrifugation where it was wash with the water for injections to remove sodium slats for the selected time.
[0038] A process according to 37 the sodium slats is sodium chloride.
[0039] A process according to claim 37 the selected time is 15 hours.
[0040] The Hydrolysis process was carried out by following steps: (a) the wet cake produce from claim 13 was taken in water for injection for selected time at room temperature; (b) in this solution the addition of sucrose was carried out with constant stirring; (c) the hydrochloric acid was added in this solution and stir for selected time; (d) add more hydrochloric acid to get the selected molarity level; (e) stir for 6 hours at

temperature 30 to 35 °C; (f) add sodium hydroxide to get the pH between 5.25 to 5.35 and then stir at room temperature for 10 minutes.
[0041] A process according to 40 (a) the selected time is 30 minutes.
[0042] A process according to 40 (c) the selected time is 15 minutes.
[0043] A process according to 40 (d) the selected molarity level is 1.65 to 1.70.
[0044] The product from claim 40 was taken for the process of centrifugation where it was wash with the water for injections to remove sodium slats for the selected time.
[0045] A process according to 44 the sodium slats is sodium chloride.
[0046] A process according to 44 the selected time is 30 hours.
[0047] The Complexation process was carried out by following steps: (a) with the help of sucrose and sodium hydroxide with the wet cake which was made by the claim 20 at the selected temperature, selected pH and the selected time; (b) the wet cake from claim 20 was dissolved in water for injection for 15 min; (c) sucrose solution was added in the solution made by 23 (a) in by adding the sodium hydroxide to adjust the pH between 11.0 to 11.50; (d) the solution was heated for the selected time and selected temperature; (e) check the molecular weight of the product produce from the claim 23 (d) after 4 hours; (f) cool the solution made up from the claim 23 (e) at selected temperature; (g) the solution made from claim 23 (f) was pass form the filter 0.2 filter cartridge; (g) the solution made from claim 23 (f) was adjusted for the pH between 11.00 to 11.50 by adding sodium hydroxide.
[0048] The isolation was carried out with product made by 47 (f) was mixed with the organic solvents between 2 to 6 hours stirring.
[0049] As per the process of 48, the organic solvents are Acetone, alcohol, Iso propyl alcohol.
[0050] A product from 49 was centrifuge to remove the mixture of water for the injection and organic solvent.
[0051] A centrifuge product was dry at selected temperature, for selected time and for selected pressure.
[0052] A process claim in 51, the selected temperature is 80 °C.

[0053] A process claim in 51, the selected time is 6 hours.
[0054] A process claim in 51, the selected pressure is 0.2 mmHg vacuum.
[0055] A Final product according to claim 52, wherein the iron sucrose complex contain from about 4.5 to 7 % ferric iron by weight.
[0056] Preferably, the pharmaceutical composition of the invention comprises an iron sucrose complex prepared by the process according to the present invention.
Definitions
[0057] The term "excipients" as used herein refers to components of the product of a process of the invention that are other than iron sucrose complex. Examples include, free sucrose, water and solvents, and substances related to the synthesis process. By "substances related to the synthesis process" is meant the reagents used in the synthesis and products of degradation of either the synthesis reagents of the reaction products.
[0058] The term "base" as employed herein refers to a chemical species that donates electrons or hydroxide ions (Arrhenius definition) or that accepts protons (Bronsted definition). Bases include strong bases, i.e., bases that are completely dissociated in aqueous solution and weak bases, i.e., bases that are only partially dissociated in aqueous solution. Examples of strong bases include sodium hydroxide and potassium hydroxide. Examples of weak bases include ammonia and alkyl amines.
[0059] The expression "water-miscible organic solvent," unless otherwise indicated, refers to an organic solvent, which is soluble in water in all proportions at standard temperature and pressure. Suitable water-miscible organic solvents include, for example, methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, dioxane, dimethyl formamide, dime thy lace tamide, and N-methylpyrrolidinone.
5) DETAILED DESCRIPTION OF THE INVENTION
[0060] The present invention provides a process for the preparation of iron sucrose complexes. The iron sucrose complexes can be used to formulate a therapeutic iron sucrose composition containing lower levels of contaminants.

[0061] A. Ferric Chloride
The ferric chloride can be used as different names like flores martis, iron chloride, Iron (III) choloride, Iron (III) chloride solution, iron sesquichloride, Iron trichloride.
[0062] A. Ferric Hydroxide
[0063] The term "ferric hydroxide" as employed herein, includes the various forms of ferric hydroxide, including, for example, hydrated ferric oxide, ferric oxy hydroxide, polymeric ferric hydroxide, ferric hydroxide gel, partially neutralized ferric salts and partially neutralized polymeric ferric salts.
[0064] B. Preparation of Ferric Hydroxide
[0065] The ferric hydroxide utilized as the starting material in the process of the present invention may be prepared by reacting a ferric salt with at least about one molar equivalent of a base, based on the amount of the ferric salt. A mixture of ferric salts, and/or a mixture of bases, may be employed. Suitable ferric salts include ferric salts wherein the anion is an anion of an acid such as, for example, chloride, bromide, iodide, nitrate, sulfate, acetate, citrate and other acid anions. Preferred ferric salts include, for example ferric chloride and ferric nitrate.
[0066] Suitable bases for reaction with the ferric salt include, for example, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, water-soluble amines and mixtures thereof. Preferred bases include sodium carbonate, sodium bicarbonate, sodium hydroxide, tris-hydroxymethyl-aminoethane and mixtures thereof.
[0067] The ferric hydroxide may be prepared by (a) providing a reaction mixture comprising a ferric salt dissolved in an aqueous medium; (b) adding to the reaction mixture a base with ferric salt in presence of water for injection; (c) allowing the reaction mixture to equilibrate for a time interval greater than about 15 minutes (d) collecting the ferric hydroxide from the reaction mixture.
[0068] The base may be the same, or may be different bases. The base may be added to the reaction mixture in solution or suspension in an aqueous solvent. Alternately the bases may be added neat, i.e., a base such as sodium carbonate may be added as a dry solid.
[0068] The base may be added to the reaction mixture batchwise, i.e., all at once, or continuously or semi-continuously over a time interval at a

constant or variable addition rate. A slow continuous addition may be performed as a titration wherein the pH of the mixture is continuously monitored, preferably using a pH meter. The addition of the base may be stopped when a selected pH, preferably about 8.0 + 0.1 came.
[0069] After the addition of the first base to the reaction mixture, the reaction mixture is allowed to equilibrate, with or without stirring. The temperature is preferably maintained in the range from about 30 degree to about 35 degree C. The pH of the reaction mixture is typically observed to drop to a pH in the range from about to about 8.0 + 0.1 during the time interval when the reaction mixture is allowed to equilibrate.
[0070] Following complete addition of the base, the reaction mixture, comprising a suspension of ferric hydroxide, is allowed to equilibrate for a time interval from about 15 minutes. The ferric hydroxide precipitate is observed to settle during the equilibration period.
[0071] The ferric hydroxide precipitate may be collected from the reaction mixture by any suitable method, including, for example, filtration, centrifugation, or decanting. Filtration is preferred. Suitable filtration methods include vacuum filtration, e.g., for example through a Buchner funnel. The resulting filter cake comprising ferric hydroxide is washed with water for injection.
[0072] To prepare iron sucrose, a suspension or slurry of ferric hydroxide, as prepared above, is reacted with sucrose in a reaction mixture comprising sodium ions. The sucrose is preferably provided as a solution of sucrose in an aqueous solvent. The sodium ions are preferably provided by addition of a sodium base, preferably aqueous sodium hydroxide. The mixture of the ferric hydroxide and sucrose may become basic upon the addition of the sodium base. The sodium base may be added to the aqueous medium, and the ferric hydroxide may subsequently be added. Alternately, the sodium base may be added to the mixture of the ferric hydroxide and sucrose in the aqueous medium.
[0073] The reaction mixture is optionally heated to a temperature in the range from about 30degree to about 35 degree C, prior to the step of isolating iron sucrose complex from the reaction mixture.
[0074] The reaction of ferric hydroxide and sucrose may be optionally monitored to determine the weight average molecular weight and purity of the iron sucrose product. Removing an aliquot of the reaction mixture and conducting a molecular weight analysis on the aliquot was done for monitoring.

[0075] When the reaction of ferric hydroxide and sucrose is complete (as determined by observation of the clarity of the reaction mixture) the iron sucrose complex is isolated from the reaction mixture. Isolation may be achieved by adding one or more water-miscible organic solvents to the reaction mixture to precipitate the iron sucrose complex. Suitable methods for collecting the product include, for example, filtration, centrifugation and decanting. The product is preferably collected by filtration. The selection of suitable filtration media, e.g., for example, a sintered glass funnel or Buchner funnel, is within the capability of one of ordinary skill in the art.
[0076] Alternately, the iron sucrose complex is isolated from the reaction mixture by concentrating the reaction mixture to form a residue comprising the iron sucrose complex. Concentration of the reaction mixture may be carried out by centrifugation method.
[0077] The centrifugation was last for about 30 hours, preferably it was 25 hours.
[0078] The wet cake of product of iron and sucrose again react with again sucrose and sodium hydroxide. The reaction was carried out at 100 degree C to 103 degree C. the pH was 10.50 to 11.50. The time for reacting the compounds was 4 hours.
[0079] The resulting complex was isolated with the organic solvents and the water for injection.
[0080] The organic solvents group which may ranging from methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, dioxane, dimethyl formamide, dimethylacetamide, and N-methylpyrrolidinone.
[0081] According to the invention, there is provided a pharmaceutical composition in solid dosage form comprising a pharmaceutically acceptable carrier and an iron sucrose complex having a molecular weight in the range from about 20,000 to about 400,000 Daltons. The pharmaceutical composition of the invention may be formulated for oral administration and may be in the form of a tablet, capsule, pill, powder, granule or other suitable solid dosage form with suitable excipients and additives.
[0082] The pharmaceutical composition according the invention comprises an iron sucrose complex that contains from about 1 to about 33.33% ferric iron by weight.

[0083] The practice of the invention is illustrated by the following examples.
Example 1
Preparation of Iron Sucrose Complex
[0084] To a solution of ferric chloride Anhydrous (12.6 gm) in WFI (200 ml) is added sodium carbonate (12.4 gm) solution in WFI (100 ml) with continue stirring and the pH was about 3.80.
[0085] The colloidal ferric oxyhydroxide formed is washed several times with water to remove the chloride salt (check with silver nitrate solution). Then ferric oxyhydroxide is suspended in 500 ml of water and added 50 gm sucrose in 200 ml WFI at 25° C.
[0086] The mixture is stirred about 5 minutes. Then the pH is brought to 10.5 by 10% NaOH solution.
[0087] Then the reaction mixture is heated for 6 hrs. At 100°C. Cool the solution at 30°C and filter by 0.45µm filter paper.
Example 2
Preparation of Iron Sucrose Complex
[0088] To a solution of ferric chloride Anhydrous (12.6 gm) in WFI (200 ml) is added sodium carbonate (12.4 gm) solution in WFI (100 ml) with continue stirring (pH = 3.80).
[0089] The colloidal ferric oxyhydroxide formed is washed several times with water to remove the chloride salt (check with silver nitrate solution).
[0090] Then ferric oxyhydroxide is suspended in 500 ml of water and added 50 gm sucrose in 200 ml WFI at 25° C.
[0091] The mixture is stirred about 5 minutes. Then the pH is brought to 10.5 by 10% NaOH solutions.
[0092] Then the reaction mixture is heated for 6 hrs. At 100°C. Cool the solution at 30°C and filter by 0.45µm filter paper.
[0093] After that pass solution in ultra filtration cassette. Then isolated by Acetone.
Example 3

Preparation of Iron Sucrose Complex
[0094] Step-I Preparation Of Ferric hydroxide:
[0095] Clean 2 liter round bottom flask with water for injection and check conductivity (NMT2 .0 uS). Take 100 ml water for injection and to it add 12.6 gm Ferric chloride portion wise under constant stirring such that the temperature is maintained at 30 °C throughout the addition (Take care as exothermic reaction takes place). Take 45 ml water for injection and to it add 12.6 gm sodium carbonate slowly under constant stirring such that the temperature is maintained at 30 °C throughout the addition. Adjust pH of the Ferric Chloride solution by adding the sodium carbonate solution to 8.0 ±0.1 under constant stirring at less than 30 °C. Stir the above solution for 10 mins. Filter and was wash with WFI up to chloride removed. (Check by titration with 0.01 M silver nitrate in Filtrate).
[0096] Step-II Hydrolysis
[0097] Take wet cake in 250 mL WFI and Dissolve 50gm sucrose in 25 ml water for injection and add this solution to the solution obtained above under constant stirring. Adjust the Molarity of above solution to 1.2 to 2.0 with 8N Hydrochloric acid (Check by titrating against 0.1 M sodium hydroxide). Approx. 100 ml of 8N hydrochloric acid is required.. Clean 2.0-litre round bottom flask with water for injection and check conductivity (NMT 2 .0 uS). Stirring for 2 hours at room temp. ( 25 -30 ° C ). Adjust the pH of the reaction mass to 5.25 - 5.35 by 4N sodium hydroxide.. The crude product is obtained. Stir at room temp for 10 minutes. Filter it and wash with water for injection till the chloride is removed. (Check by titration with 0.01 M silver nitrate in Filtrate). Collect the wet cake for next step.
[0098] Step-Ill Cornplexation:
[0099] Dissolve the wet cake obtained in 40 ml water for injection and add sucrose solution (100 gm sucrose in 50 ml Water for injection) and adjust the pH to 11.5 by 4N sodium hydroxide. Start heating and maintain heating the above solution for 4 hrs at 100°C. Cool the solution to RT within 30 minutes. Filter through 0.2 micron filter membrane. And collect solution for isolation.
[0100] Step- IV Isolation:

[0101] Clean 20 -lit round bottom flask with water for injection and check conductivity (NMT 2.0 pS). Add 1.6-liter acetone and start stirring. Add the solution obtained in Step II drop wise within 6 hrs with constant stirring. Stir for 2 hrs after addition is complete. Stop the stirring. Filter the solution and wash with Fresh Acetone. Collect the Powder.
[0102] Step-V Drying
[0103] Clean the vacuum oven and check vacuum and temperature. Put the powder in tray and dry it at 80° C for 6 hrs. Final collect dry powder in plastic Jar.
Example 4
Preparation of Iron Sucrose Complex
[0104]Step-I Preparation Of Ferric hydroxide:
Clean 5 liter round bottom flask with water for injection and check conductivity (NMT 2 .0 uS). Take 500 ml water for injection and to it add 100 gm Ferric chloride portion wise under constant stirring such that the temperature is maintained at 30 °C throughout the addition (Take care as exothermic reaction takes place). Take 450 mL water for injection and to it add 110 gm sodium carbonate slowly under constant stirring such that the temperature is maintained at 30 °C throughout the addition. Adjust pH of the Ferric Chloride solution by adding the sodium carbonate solution to 8.0 + 0.1 under constant stirring at less than 30 °C. Stir the above solution for 10 mins. Add 1.2 liter of WFI and stirring for 2 hrs at room temp. Filter and was wash with WFI up to chloride removed. (Check by titration with 0.01 M silver nitrate in Filtrate).
[0105] Step-II Hydrolysis
[0106] Clean 2.0-litre round bottom flask with water for injection and check conductivity (NMT 2 .0 uS) Take wet cake in 500 mL WFI and Dissolve 400gm sucrose in 200 ml water for injection and add this solution to the solution obtained above under constant stirring. Adjust the Molarity of above solution to 1.65 to 1.7 with 8N Hydrochloric acid (Check by titrating against 0.1 M sodium hydroxide). Approx. 300 ml of 8N hydrochloric acid is required.. Stirring for 2 hours at room temp. ( 25 -30 ° C ). Adjust the pH of the reaction mass to 5.25 - 5.35 by 4N sodium hydroxide.. The crude product is obtained. Stir at room temp for 10 minutes. Filter it and wash with water for injection till the chloride is removed. (Check by titration with 0.01 M silver nitrate in Filtrate). Collect the wet cake for next step.

[0107] Step-Ill Complexation:
[0108] Clean 2.0-litre round bottom flask with water for injection and check conductivity (NMT 2.0 uS). Dissolve the wet cake obtained in 300ml water for injection and add sucrose solution 200 gm sucrose in 100 ml Water for injection and adjust the pH to 11.5 by 4N sodium hydroxide. Start heating and maintain heating the above solution for 4 hrs at 100°C. Cool the solution to RT within 30 minutes. Filter through 0.2 micron filter membrane. And collect solution for isolation.
[0109] Step- IV Isolation:
[0110] Clean 20 -lit round bottom flask with water for injection and check conductivity (NMT 2.0 uS). Add 11-liter acetone and start stirring. Add the solution obtained in Step II drop wise within 6 hrs with constant stirring. Stir for 2 hrs after addition is complete. Stop the stirring. Filter the solution and wash with Fresh Acetone. Collect the Powder. [0111] Step-IV Drying
[0112] Clean the vacuum oven and check vacuum and temperature. Put the powder in tray and dry it at 80° C for 6 hrs. Final collect dry powder in plastic Jar.
Example 5
Preparation of Iron Sucrose Complex
[0113] Step - I Preparation of ferric hydroxide
[0114] Clean 50 liter RBF-1 with Water for injections and check conductivity (Not more than 2.0 uS at 25°C)
[0115] Send the sample in QC for conductivity. After release from QC start further process.
[0116] Take 5.0 Litres Water for injections and to it add 1.0 Kg Ferric chloride portion wise under constant stirring for 15 minutes after last portion addition of FeCl3 such that the temperature is maintained at between 30° and 35°C throughout the addition (Take care as exothermic reaction takes place).
[0117] Take 4.5 Liters Water for injections and to it add 1.10 Kg sodium carbonate slowly
under constant stirring such that the temperature is maintained at 30 °C throughout the addition.

[0118] Adjust pH of the Ferric Chloride solution by adding the sodium
carbonate
solution to 8.0 + 0.1 under constant stirring at less than 30 °C.
[0119] Note: Send the sample for pH analysis only after precipitation of
Fe(OH)3 took
place. Sample quantity shall not be more than 50 mL.
[0120] Stir the above solution for 2 hrs.
[0121] Centrifuge
[0122] Clean Centrifuge with Water for injections and check conductivity (Not more than 2.0 pS at 25°C )
[0123] Send the sample in QC for conductivity. After release from QC, start further process.
[0124] Centrifuge the above solution and wash with Water for injections at least for 15 hours.
[0125] Continue the process till chloride is removed.
[0126] Send the sample in QC after 15 hours for the chloride test.
[0127] After QC release, start further process.
[0128] Collect the wet cake for next step.
[0129] STEP - II HYDROLYSIS
[0130] Clean 50-litre RBF-1 with Water for injections and check conductivity (Not more than 2.0 uS at 25°C )
[0131] Send the sample in QC for conductivity. After release from QC start further process.
[0132] Take wet cake from step - I and dissolve 5 liter WFI and stirring for 30 min at room temp.
[0133] Add 3 Kg sucrose in this solution under constant stirring.
[0134] Add approximately 2.5 liter 8N hydrochloric acid in the above slurry.

[0135] Stir for 15 minutes
[0136] Send the sample in QC for the analysis of Molarity of the above solution against 0.1 M sodium hydroxide.
[0137] Molarity shall be between 1.65 and 1.75. If not add stepwise quantity of 8N Hydrochloric acid & repeat the process.
[0138] Stirring for 6 hours at 30- 35° C.
[0139] After 6 hrs stirring Adjust the pH of the reaction mass to 5.25 -5.35 by 4N sodium hydroxide. An approx. 4.0 to 4.5 liter of sodium hydroxide is consumed.
[0140] The crude product is obtained. Stir at room temp for 10 minutes.
[0141] CENTRIFUGE
[0142] Clean Centrifuge with Water for injections and check conductivity (Not more than 2.0 uS at 25°C)
[0143] Send the sample in QC for conductivity. After release from QC start further process.
[0144] Centrifuge the above solution and wash with Water for injections at least for 30 hours.
[0145] Continue the process till chloride is removed.
[0146] Send the sample in QC after 25 hours for the chloride test.
[0147] After QC release, start further process.
[0148] Collect the wet cake for next step.
[0149] STEP-III COMPLEXATION
[0150] Clean 50-litre RBF-II with Water for injections and check conductivity (Not more than 2.0 uS at 25°C )
[0151] Send the sample in QC for conductivity. After release from QC start further process

[0152] Dissolve the wet cake obtained from step - II in 3-liter water and stirring for 15 min.
[0153] Add sucrose solution (2.5 kg sucrose in 1 liters Water for injections) and adjust the pH to 11.00 to 11.50 by 4N sodium hydroxide.
[0154] Heat the above solution for 4 hrs at 100 - 103°C.
[0155] During reflux check the pH of the solution every hours, pH shall be 10.5 to 11.0 during reflux. Adjust the pH if required by addition of 4N NaOH solution.
[0156] Check the molecular weight after 4 hrs.
[0157] Cool the solution upto 40°C to 50°C.
[0158] Filter through 0.2 filter cartridge. After filtration check pH the solution. pH shall be 11.00 to 11.50 Adjust the pH if required by addition of 4N NaOH solution.
[0159) Collect the solution for next step.
[0160] STEP - IV ISOLATION
[0161] Clean 200-Iit RBF-III with Water for injections and check conductivity (Not more than 2.0 pS at 25°C )
[0162] Send the sample in QC for conductivity. After release from QC start further process
[0163] Add 110-liter acetone after filtration through 0.2 □ filter cartridge and start stirring.
[0164] Add the solution obtained in Step III (Complexation solution) drop wise within 6 hrs with constant stirring.
[0165] Stir for 2 hrs after addition is complete.
[0166] Stop the stirring.
[0167] CENTRIFUGE
[0168] Clean Centrifuge with Water for injections and check conductivity (Not more than 2.0 pS at 25°C)

[0169] Send the sample in QC for conductivity. After release from QC start further process.
[0170] Centrifuge it and wash with 5.0 liter fresh acetone.
[0171] Collect the wet cake for next step.
[0172] Clean the vacuum oven and check vacuum and temperature.
[0173] Put the powder in tray and dry it at 80° C for 6 hrs at 0.2 mm.Hg vacuum.

6. CLAIMS:
What is claimed is:
1. A process of preparing crystalline iron sucrose complex of mol. Wt. 34000 to 60000 dalton & substantially free of excipients, comprising the steps of:
(a) Preparation of ferric hydroxide from ferric salts in presence of
water for injection at a selected ratio, time, pH and temperature,
(b) Centrifugation of the ferric hydroxide for selected time,
(c) Hydrolysis of the ferric hydroxide with sucrose in presence of the Hydrochloric acid and Sodium hydroxide to obtain solution,
(d) Centrifugation of the solution at selected temperature for selected time with water for injection to obtain a cake,
(e) Complexation of the wet cake with sugar and Sodium hydroxide at a selected temperature, selected time and selected pH,
(f) Isolation of complex is carrying out with organic solvents at selected time and selected ratio,
(g) Centrifuge the obtained product with the mixture of the water for injection and the organic solvents,
(h) Drying of the complex is carry out at selected temperature, selected pressure and for selected time.
2. A process as claimed in claim 1 wherein the the ferric salt is ferric
chloride.
3. A process as claimed in claim 1 wherein centrifugation of product
carried out remove sodium salts.
4. A process as claimed in claim 1 wherein the hydrolysis is carried out by
(a) The addition of sucrose to ferric hydroxide was carried out with constant stirring.
(b) The hydrochloric acid was added to it,

(c) Adding more hydrochloric acid to get the selected molarity level of 1.65 to 1.70 & Stir for 6 hours at temperature 30 to 35 0C;
(d) Add sodium hydroxide to get the pH between 4.5 to 5.5 and then stir at room temperature for 10 minutes.
5. A process as claimed in claim 1 wherein the Complexation process
was carried out by following steps:
(a) sucrose and sodium hydroxide with the wet cake carried out by dissolving the wet cake in water.
(c) Sucrose solution was added to it & adding the sodium hydroxide to
adjust the pH between 11.0 to 11.50.
(d) heated it for the selected time and selected temperature.
(e) Check the molecular weight of the product,
(f) Cooling the solution ,
(g) filtering the solution through the 0.2M filter cartridge.
6. A process as claimed in claim 1 wherein the isolation was carried
out with water miscible organic solvent selected from acetone,
alcohol and Iso propyl alcohol.

Documents:

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Patent Number

269965

Indian Patent Application Number

1215/MUM/2007

PG Journal Number

48/2015

Publication Date

27-Nov-2015

Grant Date

20-Nov-2015

Date of Filing

25-Jun-2007

Name of Patentee

CLARIS LIFESCIENCES LTD.

Applicant Address

CLARIS LIFESCIENCES LTD. CLARIS CORPORATE HEADQUARTERS, NR. PARIMAL CROSSING, ELLISBRDGE, AHMEDABAD.

Inventors:

#	Inventor's Name	Inventor's Address
1	MAJUMDAR CHETAN S	CLARIS LIFESCIENCES LTD. CLARIS CORPORATE HEADQUARTERS, NR. PARIMAL CROSSING, ELLISBRDGE, AHMEDABAD-380006.
2	BOSE MILINA	CLARIS LIFESCIENCES LTD. CLARIS CORPORATE HEADQUARTERS, NR. PARIMAL CROSSING, ELLISBRDGE, AHMEDABAD-380006.
3	KALAWADIA RAMESH M	CLARIS LIFESCIENCES LTD. CLARIS CORPORATE HEADQUARTERS, NR. PARIMAL CROSSING, ELLISBRDGE, AHMEDABAD-380006

PCT International Classification Number

A61K31/7016

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA