DESC:FIELD OF THE INVENTION

The present application relates to an improved process for the preparation of iron carbohydrate complex. The present application more particularly relates to an improved process for the preparation of iron sucrose complex.

BACKGROUND OF THE INVENTION

Iron carbohydrate complexes for IV therapy consist of nanosize range particles with a polynuclear Fe(III)-oxyhydroxide core and a carbohydrate shell. Iron carbohydrate complexes are nanomedicines or nanocolloidals.
The carbohydrate shell surrounding the iron plays crucial roles in stabilizing the iron core, slowing down the release of bioactive iron, protecting the particles from further aggregation, as well as sustaining the particles in a colloidal suspension. Since the advent of intravenous iron complexes, various types of carbohydrates have been selected for these nanomedicines, including dextran, gluconate, sucrose, carboxymaltose, isomalto-oligosaccharide, and polyglucose sorbitol carboxymethyl ether.

There are five types of injectable iron-carbohydrate complex products currently approved by the USFDA which are INFeD®/Dexferrum® (Iron dextran), Ferahem® (ferumoxytol), Injectafer® (ferric carboxymaltose), Venofer® (Iron sucrose) and Ferrlecit® (Sodium ferric gluconate complex).

USFDA approved Venofer® as iron sucrose complex in the year 2000. Preparation of iron sucrose complex having molecular weight between 34000-60000 Daltons and structural formula [Na2Fe5O8 (OH).3(H2O)]n. m(C12H22O11) wherein n is degree of polymerization and m is the number of sucrose molecules associated with the iron(III)hydroxide is an important therapeutic complex widely used to treat iron deficiency anemia in patients with chronic kidney disease (CKD).

US 3,821,192 (Montgomery et.al) discloses a process for preparing a stable, soluble complex of iron with glucose, maltose and dextrin. However it does not include sucrose. They used ferric hydroxide derived from ferric chloride and polymerized in presence of carbohydrate at pH 11.0 - 14.0 followed by concentration with organic solvent and filtration.

US 7,674,780 discloses another method for preparation of Iron sucrose comprising of addition of an inorganic base to an aqueous solution of ferric salts to obtain ferric hydroxide followed by addition to an aqueous solution of sucrose and heating at a temperature of 100 - 105oC, followed by freeze drying of the resulting product. The iron sucrose thus obtained has to be purified to obtain the product conforming to desired specifications. Further freeze drying method is not suitable for industrial purpose and also this method is very expensive.

CN103059072B discloses a process of preparing iron sucrose complex which uses ion exchange resin to purify the product. The use of resins makes the operation more complicated and also increases the production cost.

CN104098616B discloses a preparation method of iron sucrose complex. However molecular weight of iron sucrose complex prepared by this method does not meet the requirements as per USP40 (US Pharmacopoeia 40th Edition)

Following references also disclose processes for the preparation of Iron Sucrose: US 7,964,568; US 7,674,780; US 8,053,470; US 20080167266; WO 2009078037; US 8,030,480; US20150141630; US20180147238; IN 187116; US 11111261 and US 8,053,470. US 7674780 isolate the Iron sucrose complex by precipitating using ethanol as a solvent, in order to precipitate the patent utilizes about 70 volume of ethanol w.r.t. ferric chloride hexahydrate used as a starting material. Since the volume of ethanol requirement is high, this process is not suitable for commercial manufacturing and reducing the quantity of solvent either yields impure products or no precipitation is observed. The similar observation is observed in most of the solvents like acetone, acetonitrile, 1,4-dioxane, ethylene glycol, tetrahydrofuran, methanol, 1-propanol, and 2-propanol.

It has been reported in the literature that the toxicity of iron sucrose complex is related to molecular weight and molecular stability (see Fishbane et al., Semin Dial. 2000Nov-Dec; 13(6):3814.), the molecular weight of iron sucrose prepared in the prior art is concentrated in 34000 – 60000 Dalton, with a wide molecular weight distribution. Although it is relatively stable in general, it has very strict requirements for storage and transportation conditions. Commercially available Venofer® also state that incorrect storage can lead to the formation of visible deposits. It can be seen that there is a need for developing a method for synthesizing iron sucrose, which has better safety and stability by controlling the molecular weight distribution of iron sucrose.

The present invention provides an improved process for the preparation of iron sucrose complex which provides predictable and reproducible control of the molecular weight range of iron sucrose obtained by the process, easy to handle at large scale synthesis with minimizing the solvent volume as well as overall cost of the process.

The present invention further provides an improved process for preparing iron carbohydrate complex compounds.

SUMMARY OF THE INVENTION
In one aspect, the present invention provides an improved process for the preparation of Iron carbohydrate complex comprising the steps of:
i) providing a reaction mass comprising of iron carbohydrate complex and water;
ii) adding water-miscible suitable organic solvent(s) to the reaction mass;
iii) isolating iron carbohydrate complex and optionally purifying the complex product,
wherein the water-miscible suitable organic solvent(s) used is glycol ethers selected from 2-methoxyethanol or 2-ethoxyethanol.

In another aspect, the present invention provides an improved process for the preparation of Iron sucrose complex having molecular weight of 34,000 to 60,000 daltons comprising the steps of:
i) reacting ferric salt with base to obtain ferric oxy-hydroxide;
ii) adding ferric oxy-hydroxide obtained in step (i) in water;
iii) preparing alkaline sucrose solution by treating aqueous sucrose solution with sodium hydroxide;
iv) reacting alkaline sucrose solution obtained in step (iii) with ferric oxy-hydroxide in water obtained in step (ii) to form iron sucrose complex;
v) isolating iron sucrose complex using adding water-miscible suitable organic solvent(s), wherein the water-miscible suitable organic solvent(s) added is about 25 volume to 30 volume with respect to ferric salt.

In yet another aspect, the present invention further provides an improved process for the preparation of iron sucrose complex having molecular weight of 34,000 to 60,000 daltons and having OVI (organic volatile impurity) content of 2-methoxyethanol is 0.1 ppm to less than 50 ppm comprising the steps of:
i) providing a reaction mass comprising of iron sucrose complex and water;
ii) adding 2-methoxy ethanol to the reaction mass;
iii) isolating iron sucrose complex; and
iv) optionally purifying the iron sucrose complex obtained.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustration of a PXRD pattern of crystalline form of Iron sucrose complex obtained from example-1.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that the invention is not limited in its application to the details set forth in the following description or exemplified by the examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.

In one embodiment, the present invention provides an improved process for the preparation of Iron sucrose complex having molecular weight of 34,000 to 60,000 daltons comprising the steps of:
i) reacting ferric salt with base to obtain ferric oxy-hydroxide;
ii) adding ferric oxy-hydroxide obtained in step (i) in water;
iii) preparing alkaline sucrose solution by treating aqueous sucrose solution with sodium hydroxide;
iv) reacting alkaline sucrose solution obtained in step (iii) with ferric oxy-hydroxide in water obtained in step (ii) to form iron sucrose complex;
v) isolating iron sucrose complex using water-miscible suitable organic solvents(s).

The step (i) involves addition of aqueous sodium carbonate to aqueous ferric salt solution. The pH of the reaction is maintained in the range of 5.0 – 7.0 till the complete precipitation of ferric oxy-hydroxide. The reaction is carried out within temperature range of 15 - 25oC. The ferric oxy-hydroxide precipitates obtained is filtered and washed with water. The precipitates may be collected from reaction mixture by any suitable method selected from filtration, centrifugation or decanting.

The ferric salt used in step (i) include ferric salts wherein the anion is an anion of an acid such as chloride, bromide, iodide, nitrate, sulfate, acetate, citrate and other known acid anions. Preferred salt include, for example ferric chloride hexahydrate.

The base used in step (i) include, for example, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides such as sodium carbonate, sodium bicarbonate, sodium hydroxide and like. Preferred base include, for example sodium carbonate. The base may be added to the reaction mixture i.e. all at once, or over a time interval or lot wise. The addition of base may be stopped when desired pH range of reaction mixture is achieved.

The step (ii) involves addition of ferric oxy-hydroxide to water along with stirring to form slurry.

The step (iii) involves preparing alkaline sucrose solution by adding aqueous sodium hydroxide solution to solution of sucrose in water.

The step (iv) involves addition of slurry of ferric oxy-hydroxide in water to preheated alkaline sucrose solution or vice-versa. The pH of the reaction is maintained in the range of 10 - 12. The reaction is carried out within temperature range of 25 - 100oC. The reaction mass containing iron sucrose complex is subsequently used further for isolation and purification process.

When the reaction of ferric hydroxide and sucrose is complete, then step (v) involves isolation of iron sucrose complex from the reaction mixture. Isolation may be achieved by adding one or more water-miscible suitable organic solvents to the reaction mixture to precipitate the iron sucrose complex. The product iron sucrose complex that precipitates from the reaction mixture after addition of the water-miscible organic solvent is collected from the reaction mixture.

Preferably, the iron sucrose complex is isolated from the reaction mixture first by concentrating the reaction mixture to form a residue comprising the iron sucrose complex having reaction mass from about 4 to 10 volumes, more preferably from about 6 to 7 volumes. Concentration of the reaction mixture may be carried out at reduced pressure or at atmospheric pressure, utilizing concentration techniques such as, but not limited to distillation. The concentration of the reaction mixture is preferably done at a temperature from about 25° to about 105° C., more preferably at a temperature from about 35° to about 105° C, preferably a pressure in the range from about 10 millitorr to about 50 torr, more preferably in the range from about 10 millitorr to about 10 torr, most preferably from about 10 millitorr to about 1 torr, followed by isolation of iron sucrose complex from the reaction mixture by adding one or more water-miscible suitable organic solvents to the reaction mixture to precipitate the iron sucrose complex. The amount of water-miscible organic solvent added to the reaction mixture is preferably in the range of from about 20 volumes to about 30 volumes w.r.to ferric salt is added. For example, the amount of water-miscible organic solvent added to the reaction mixture preferably in the range of about 20 ml to about 30 ml w.r.to 1 gm of ferric salt.

The product iron sucrose complex that precipitates from the reaction mixture after addition of the water-miscible organic solvent is collected from the reaction mixture.

The water-miscible suitable organic solvent used in step (v) is glycol ethers selected from 2-methoxyethanol or 2-ethoxyethanol; more preferably uses 2-methoxyethanol for isolation of desired product.

Following are the advantages of using 2-methoxy ethanol:
1. Product solubility is very less in this solvent
2. Industrially more feasible
3. Leads to better precipitation with less volume of the solvent and cost effective.
4. Removes sucrose during precipitation leading to enrichment of iron content in the product.

Iron sucrose thus obtained is optionally purified by adding iron sucrose complex to water followed by addition of water-miscible solvent such as ethanol, methanol, propanol, butanol or mixture thereof. The precipitates formed are filtered and washed with water-miscible solvent and dried to obtain desired product.

Iron sucrose obtained according to the invention is having 0.1 ppm to 50 ppm of 2-methoxyethanol as analyzed by GC method.

Wherever applicable in the example of the present invention, the reaction solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities absorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as celite® or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

The present invention adopts following general method for the isolation such as methods including cooling, crash cooling, concentrating the mass, adding an anti-solvent, fractional distillation or evaporation or the like or combinations thereof. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.

The present invention process provides several other advantages over existing prior art processes such as obtaining desired molecular weight range, avoiding use of costly isolation techniques such as freeze drying, minimum use of solvent and also easy to execute on large scale synthesis.

EXAMPLES

The following examples are provided here to enable one skilled in the art to practice the invention and merely illustrate the process of this invention. However, it do not intended in any way to limit the scope of the present invention.

Example-1: Preparation of Iron sucrose complex:

Step-1: Preparation of Ferric hydroxide
To the stirred solution of ferric chloride hexahydrate (80.0 g) in water (400 ml) at 20oC was added 30% aqueous sodium carbonate solution (52.0 g in 176 ml water) till the pH of the solution is within 5 to 7. After completion of reaction, the precipitates formed are filtered and washed with water. The filtered cake was added to water (800 ml) to form slurry.

Step-2: Preparation of Iron sucrose complex
To solution of sucrose (480 g) in water (240 ml), was added 72 ml of 20% sodium hydroxide solution and the reaction was heated to about 100-105oC. The slurry obtained in step-1 is added to pre-heated alkaline sucrose solution along with stirring. After completion of reaction, the reaction mixture is subsequently cooled to 20-25°C and filtered to obtain the filtrate.
Step-3: Isolation of Iron sucrose complex
The filtrate obtained in step-2 is concentrated under reduced pressure to 6 volumes. 2-methoxyethanol (2000 ml) is added to this concentrated reaction mass and the precipitates formed are filtered, washed with 2-methoxyethanol (100 ml) and methanol (400 ml) and dried under vacuum to obtain crude solid compound.
The crude solid compound is further dissolved in water (1.2 volume) and ethanol (15 volume) is added with stirring to form precipitates, which is filtered and washed with methanol and dried under vacuum to obtain pure iron sucrose complex. (Content of 2-methoxyethanol: 20ppm)

Example-2: Preparation of Iron sucrose complex:

Step-1: Preparation of Ferric hydroxide
To the stirred solution of ferric chloride hexahydrate (20.0 g) in water (100 ml) at 20oC was added 30% aqueous sodium carbonate solution (36 ml). After completion of reaction, the precipitates formed are filtered and washed with water. The filtered cake was added to water (90 ml) to form slurry.

Step-2: Preparation of Iron sucrose complex
To solution of sucrose (120 g) in water (60 ml), was added 18 ml of 20% sodium hydroxide solution and the reaction was heated to about 100-105oC. The slurry obtained in step-1 is added to pre-heated alkaline sucrose solution along with stirring. After completion of reaction, the reaction mixture is subsequently cooled to 20-25°C and filtered to obtain the filtrate.

Step-3-1: Isolation of Iron sucrose complex

The filtrate obtained in step-2 is concentrated to under reduced pressure. Mixture of methanol and 2-propanol is added to this concentrated reaction mass or vice versa and the precipitates formed are filtered, washed with methanol (50 ml) and dried under vacuum to obtain powdered iron sucrose complex.

Step-3-2: Isolation of Iron sucrose complex

The filtrate obtained in step-2 of example-2 is further concentrated under reduced pressure. Mixture of methanol and 1-propanol is added to this concentrated reaction mass or vice versa and the precipitates formed are filtered, washed with methanol and dried under vacuum to obtain powdered iron sucrose complex.

Step-3-3: Isolation of Iron sucrose complex

The filtrate obtained in step-2 of example-2 is further concentrated under reduced pressure. Mixture of methanol and tetrahydrofuran is added to this concentrated reaction mass or vice versa and the precipitates formed are filtered, washed with methanol and dried under vacuum to obtain powdered iron sucrose complex.

Date this Mar. 14, 2024

Alembic Pharmaceutical Ltd
,CLAIMS:We Claim:
1. An improved process for the preparation of Iron sucrose complex having molecular weight of 34,000 to 60,000 daltons comprising the steps of:
i) reacting ferric salt with base to obtain ferric oxy-hydroxide;
ii) adding ferric oxy-hydroxide obtained in step (i) in water;
iii) preparing alkaline sucrose solution by treating aqueous sucrose solution with sodium hydroxide;
iv) reacting alkaline sucrose solution obtained in step (iii) with ferric oxy-hydroxide in water obtained in step (ii) to form iron sucrose complex;
v) isolating iron sucrose complex using water-miscible suitable organic solvent(s);
wherein the water-miscible suitable organic solvent(s) used is glycol ether selected from 2-methoxyethanol or 2-ethoxyethanol.

2. The process as claimed in step (i) of claim 1, wherein base is selected from sodium carbonate, sodium bicarbonate or sodium hydroxide.

3. The process as claimed in step (iv) of claim 1, wherein alkaline sucrose solution is added to ferric oxy-hydroxide in water or vice-versa.

4. The process as claimed in step (iv) of claim 1, wherein reaction mixture comprising iron sucrose complex is further concentrated under reduced pressure.

5. The process as claimed in step (v) of claim 1, wherein iron sucrose complex isolated is optionally purified using solvent(s) selected from water, ethanol, methanol, propanol, butanol or mixture thereof.

6. The process as claimed in step (v) of claim 1, wherein the water-miscible suitable organic solvent is 2-methoxyethanol.

7. The process as claimed in step (v) of claim 1, wherein the water-miscible suitable organic solvent is 2-ethoxyethanol.

8. An improved process for the preparation of Iron sucrose complex having molecular weight of 34,000 to 60,000 daltons and having OVI (organic volatile impurity) content of 2-methoxyethanol is 0.1 ppm to less than 50 ppm comprising the steps of:
i) providing a reaction mass comprising of iron sucrose complex and water;
ii) adding 2-methoxy ethanol to the reaction mass;
iii) isolating iron sucrose complex; and
iv) optionally purifying the iron sucrose complex.

9. The process as claimed in step (iv) of claim 8, wherein iron sucrose complex is purified using solvent(s) selected from water, ethanol, methanol, propanol, butanol or mixture thereof.

Dated this Mar. 14, 2024
Dr. S. Ganesan
Alembic Pharmaceutical Ltd