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1. (WO2016181195) IMPROVED PROCESS FOR WATER SOLUBLE IRON CARBOHYDRATE COMPLEXES
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IMPROVED PROCESS FOR WATER SOLUBLE IRON

CARBOHYDRATE COMPLEXES

Field of the Invention

The present invention provides an improved process for the preparation of water soluble trivalent iron carbohydrate complexes. In particular, the present invention provides an improved process for the preparation of Ferric carboxymaltose.

Background of the Invention

Iron deficiency anaemia (IDA) is a common haematological complication with potentially serious clinical consequences that may require intravenous iron therapy.

Ferric carboxymaltose (FCM) is a stable, non-dextran iron formulation administered intravenously in large single doses to treat IDA. It is an iron complex that consists of a ferric hydroxide core stabilized by a carbohydrate shell. It is commercially available in the market under the trade name Ferinject®

Ferric carboxymaltose has been designed to provide high iron utilisation and to have a better benefit to risk profile than iron dextran and iron sucrose therapy. In the case of iron dextran, a key risk is the reaction with anti-dextran antibodies leading to the well known dextran induced anaphylactic reactions. In the case of iron sucrose, the negative characteristics include high pH, high osmolarity, low dosage limits and the long duration of administration.

Ferric carboxymaltose allows for controlled delivery of iron within the cells of the reticuloendothelial system and subsequent delivery to the iron-binding proteins ferritin and transferrin, with minimal risk of release of large amounts of ionic iron in the serum.

U.S. Pat. No. 3,076,798 discloses a process for the preparation of iron(III)-polymaltose complex compounds. The iron(III)-polymaltose complex compound

preferably has a molecular weight in the range from 20,000 to 500,000 daltons, preferably from 30,000 to 80,000 daltons.

U.S. Patent No. 7,612,109 discloses water-soluble iron carbohydrate complexes (ferric carboxymaltose complexes) obtainable from an aqueous solution of an iron (III) salt, preferably iron (III) chloride, and an aqueous solution of the oxidation product of one or more maltodextrins using an aqueous hypochlorite solution.

PCT application No.WO2011/055374, discloses a process for the preparation of iron (III) carboxymaltose complex using ferric hydroxide.

In Netherlands article, starch 41 (1989) Nr .8, S. 303-309 transition metal ions enhance the selectivity of oxidations by H2O2 to produce polysaccharides to polydicarbonates by glycol cleavage of the C2-C3 vicinal diol moiety.

Even though many prior art processes reported methods for the preparation of Iron(III) carboxymaltose, each process has some limitations with respect to yield, purity and scale-up etc.

Objectives of the Invention

An object of the present invention is to provide an improved process for the preparation of iron carbohydrate complex having weight average molecular weight of 80 kDa to 400 kDa obtainable from oxidation of maltodextrins with peroxide and ferric hydroxide or iron hydroxide maltodextrin complex in the presence of sodium tungstate as a catalyst.

Another object of the present invention is to provide an improved process for the preparation of Ferric carboxymaltose (FCM) obtainable from oxidation of maltodextrins with peroxide and ferric hydroxide or iron hydroxide maltodextrin complex in the presence of sodium tungstate as a catalyst.

Summary of the invention

Accordingly, the present invention provides an improved process for the preparation of water soluble trivalent iron carbohydrate complex having a weight average molecular weight of 80kDa to 400 kDa obtainable from oxidation of maltodextrins using a non-hypohalite oxidising agent and ferric hydroxide or ferric hydroxide maltodextrin complex.

In another aspect, the present invention provides an improved process for the preparation of Ferric carboxymaltose (FCM) which comprises reacting an aqueous solution of Iron (III) complex and aqueous solution of oxidised maltodextrin wherein the oxidation is carried out using a non-hypohalite oxidising agent.

Detailed description of the invention

The present invention provides an improved process for the preparation of water soluble trivalent iron carbohydrate complex having a weight average molecular weight of 80kDa to 400 kDa obtainable from oxidation of maltodextrins using a non-hypohalite oxidising agent in the presence of sodium tungstate as a catalyst, at an acidic pH, and complex formation with ferric hydroxide or ferric hydroxide maltodextrin complex wherein, when one maltodextrin is present, the maltodextrin has a dextrose equivalent of between 5 and 20, and wherein, when a mixture of more than one maltodextrin is present, the dextrose equivalent of each individual maltodextrin is between 2 and 40, and the dextrose equivalent of the mixture is between 5 and 20.

In another embodiment the present invention provides an improved process for the preparation of Ferric carboxymaltose (FCM) which comprises reacting an aqueous solution of Iron (III) complex and aqueous solution of oxidised maltodextrin wherein the oxidation is carried out using non-hypohalite oxidising agent selected from hydrogen peroxide, TEMPO (2,2,6, 6-Tetramethylpiperidinyloxy) or mixture thereof at an acidic pH in the presence of Starks catalyst (Methyl trioctyl ammonium hydrogen sulphate).

In yet another embodiment the present invention provides a process for the preparation of Ferric carboxymaltose (FCM) wherein the oxidation is carried out in the presence of transition metal catalyst.

In yet another embodiment the oxidation reaction is carried out in the presence of a catalyst such as transition metal catalyst, for example sodium tungstate. Sodium tungstate used in the present invention can be anhydrous, monohydrate, dihydrate or any other variation thereof.

Specifically, the amount of catalyst is kept as low as possible in order to achieve the end product which can easily be purified, and more specifically catalytic amounts are sufficient.

Aqueous solution of Iron (III) complex of the present invention used as starting material is ferric hydroxide or polymeric ferric hydroxide maltodextrin complex.

In a preferred embodiment, the process for the preparation of Ferric carboxymaltose (FCM) according to the present invention comprises:

a) treating ferric chloride with aqueous sodium hydroxide to prepare ferric hydroxide,

b) reacting the freshly prepared step- (a) ferric hydroxide with maltodextrin and non-hypohalite oxidising agent in the presence of catalyst to give Ferriccarboxymaltose.

Preferably, a freshly prepared ferric hydroxide is used in step-(b).

In yet another preferred embodiment, the process for the preparation of Ferric carboxymaltose (FCM) according to the present invention comprises:

a) treating ferric chloride with aqueous sodium hydroxide and maltodextrin to prepare ferric hydroxide maltodextrin complex,

b) reacting ferric hydroxide maltodextrin complex prepared in step- (a) with maltodextrin and non-hypohalite oxidising agent in the presence of catalyst to give Ferric carboxymaltose.

In yet another preferred embodiment the present invention provides an improved process for the preparation of Ferric carboxymaltose (FCM) which comprises:

a) oxidizing at least one maltodextrin in an aqueous solution at a pH in the range of lto 3 and a temperature in the range of 15 to 100 °C, with hydrogen peroxide solution to form an oxidized maltodextrin solution,

b) contacting the oxidized maltodextrin solution with an aqueous solution of an iron (III) hydroxide complex and

c) raising the pH of the oxidized maltodextrin solution and iron (III) salt to a value in the range of 8 to 12

d) isolating Ferric carboxymaltose (FCM) by adding alcohol to the aqueous complex solution.

To prepare the complex of the invention, the obtained oxidized maltodextrins are reacted with ferric hydroxide. In order to do so, the oxidized maltodextrins can be isolated and re-dissolved. It is also possible to use the obtained aqueous solutions of the oxidized maltodextrins directly for further reaction with ferric hydroxide. For instance, the aqueous solution of the oxidized maltodextrin can be mixed with ferric hydroxide in order to carry out the reaction.

The oxidation may be carried out in an acidic solution, for example at a pH of 1 to 3. The oxidation may be carried out at temperatures in the range of 15 to 100°C, preferably of 50 to 90° C. The reaction may be carried out for a period of 10 minutes to 4 hours, e.g. 1 to 3 hours.

The aqueous solution of the oxidized maltodextrin can be mixed with an aqueous solution of the iron (III) salt in order to carry out the reaction. It is preferred to proceed in a manner so that during and immediately after mixing of the oxidized

maltodextrin and the iron (III) salt, the pH is moderately acidic and adjusted to an alkaline pH to a value in the range of 8 to 12, preferably 9to 11, and maintaining the reaction at a temperature of 25 to 60°C, preferably 50 to 55°C.

During the oxidation pH is initially maintained at 1 to 3 and at a temperature of 40 to 100°C, followed by adjusting the pH between 8 to 12 with an aqueous alkali hydroxide, preferably sodium hydroxide and maintaining the reaction at a temperature of 35 to 55 °C, preferably 50 to 55°C for iron complex formation. Later, the pH can be lowered to 5 to 6, preferably 5.5, by the addition of an acid and maintaining the reaction at a temperature of 35 to 125 °C, preferably 50 to 100°C. It is preferable to use inorganic or organic acids or a mixture thereof, specifically hydrohalic acids such as aqueous hydrochloric acid.

The following examples describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limitative and relate to solutions which have been particularly effective on a bench scale.

EXAMPLES

Example- 1: Preparation of trivalent iron carboxymaltose

Step (i)

20grams of anhydrous iron(III)chloride was dissolved in 50ml of purified water at room temperature for 10 minutes stirring. To this 2gm of maltodextrin (13-17 dextrose equivalents) was added and stirred for 10 minutes at room temperature. The obtained brownish-yellow clear solution was cooled to 0-5°C and the pH of the reaction mixture was adjusted to 7.0 by adding 20% aqueous sodium hydroxide solution. A brown colour precipitate obtained was maintained for 1 hour at 0-5°C and collected through filtration (Wet cake wt. ~ 65. Og). The cake was suck dried and used for next step.

Step (ii)

20grams of maltodextrin having a dextrose equivalents of 13-17 were dissolved in 50ml of purified water and the solution was metered in the course of 20 minutes to a stirred mixture of 2.66gm of Starks catalyst (methyl trioctyl ammonium hydrogen sulfate prepared in-situ from 2gm of Aliquat 336 and 0.66gm of NaHSO4.H2O), 0.8gm of sodium tungstate dihydrate and 0.37gm of TEMPO at RT. 31.12gm of hydrogen peroxide solution (50-55% w/v) was then added drop wise over a period of 40 minutes at 25-30°C and raised the temperature to90-95°C and stirred for 3 hours. After cooling to room temperature, a second portion of 15.5gm of H2O2 solution was metered in the course of 15 minutes at 25-30°C and the resulting solution was again refluxed at 90-95°C for 1 hour. After cooling to 35-40°C, wet cake of step (i) (ferric hydroxide maltodextrin complex) was added, with stirring. 14.0ml of 20% aqueous sodium hydroxide solution was added to adjust the reaction mass pH to 10- 10.5 and the slurry was heated to 50°C, stirred for 30 minutes. Then the reaction mixture was acidified to pH 5.5 by adding hydrochloric acid solution and the mixture was maintained at 50°C for another 30 minutes. Further temperature was raised to 95-100°C and stirred for 14 hours. Then the reaction mixture was cooled to room temperature and filtered through a celite pad. Thereafter, the iron(III)complex was isolated by precipitation by adding ethanol (237. Og) drop wise at room temperature. The obtained brown amorphous solid was dried under vacuum at 50°C for 2-3 hours. Molecular weight = 202 kDa. Iron content = 23.38% w/w

Example-2:

20grams of maltodextrin (13-17 dextrose equivalents) were dissolved in 50ml of purified water and the solution was added to a stirred mixture of 2.66gm of Starks catalyst and 0.2gm of Na2WO4.2H2O at room temperature in the course of 20 minutes. 24grams of H2O2 solution was metered in the course of 45 minutes at 25-30°C and raised the temperature to 90-95°C and stirred for 2 hours and cooled to room temperature.

The solution was added to another portion of a stirred mixture of 1.33gm of Starks catalyst and 0.2gm of Na2WO4.2H2O at room temperature. Thereafter, 12gm of

H2O2solution was added drop wise over a period of 20 minutes at 25-30°C and the resulting reaction mixture was again refluxed at 90-95°C for 2 hours. After cooling to 25-30°C, wet cake of step (i) from example- 1 was added and stirred for 10 minutes. 14ml of 20% NaOH solution was added to adjust the reaction mass pH to 10- 10.5 and the slurry was heated to 50°C, stirred for 30 minutes. Then the mixture was acidified to pH 5.5 by adding hydrochloric acid solution and the solution was maintained at 50°C for another 30 minutes. Further temperature was raised to 95-100°C and stirred for 13 hours. Then the reaction solution was cooled to room temperature, adjusted pH to 5.5 to 6.0 with 20% NaOH solution and filtered through a celite pad. Then the iron(III)complex was isolated by precipitating with ethanol (331.0g) addition drop wise at room temperature. The obtained brown amorphous solid was dried in vacuum at 50°C for 2-3 hours. Molecular weight = 200 kDa. Iron content = 25.57 % w/w

Example-3:

20grams of maltodextrin (13-17 dextrose equivalents) were dissolved in 100ml of purified water and the solution was added to a stirred mixture of 2.66gm of Starks catalyst, 0.8gm of Na2WO4.2H2O and 0.37gm of TEMPO at room temperature over a period of 15 minutes. 30grams of H2O2solution was added drop wise in the course of 1 hour at 25-30°C and raised the temperature to 90-95°C, stirred for 3 hours and cooled to room temperature.

At 25-30°C, wet cake of step (i) from example- 1 was added and stirred for 10 minutes. A pH of 10-10.5 was established by adding 12ml of 20% NaOH solution and the slurry was heated to 50°C, stirred at this temperature for 30 minutes. Then the reaction mixture was acidified to pH 5.5 with hydrochloric acid addition and the mixture was maintained at 50°C for another 30 minutes. Further temperature was raised to 95-100°C and stirred for 14 hours. The reaction mixture was allowed to cool to room temperature, adjusted pH to 6.0 to 6.5 with 20% NaOH solution and filtered through a celite pad. Then the iron(III)complex was isolated by precipitating with ethanol (343.0g) addition drop wise at room temperature. The obtained brown

amorphous solid was dried in vacuum at 50°C for 2-3 hours. Molecular weight = 260 kDa. Iron content = 23.67 % w/w

Example-4:

20grams of maltodextrin (13-17 dextrose equivalents) were dissolved in 50ml of purified water and the solution was added to a stirred mixture of 2.66gm of Starks catalyst, 0.8gm of Na2WO4.2H2O and 0.37g of TEMPO at room temperature over a period of 15 minutes. 30grams of H2O2 solution was added drop wise over a period of 1 hour at 55-60°C and the temperature was raised to 90-95 °C, stirred for 3 hours and cooled to room temperature. After cooling to 25-30°C, wet cake of step (i) from example- 1 was added and stirred for 10 minutes. A pH of 10-10.5 was established by adding 12ml of 20% NaOH solution and the slurry was heated to 50°C, stirred at this temperature for 30 minutes. Then the reaction mixture was acidified to pH 5.5 with hydrochloric acid addition and was maintained at 50°C for another 30 minutes. Further temperature was raised to 95-100°C and stirred for 12 hours. The reaction mixture was allowed to cool to room temperature, adjusted pH to 6.0 to 6.5 with 20% NaOH solution and filtered through a celite pad. Then the iron(III)complex was isolated by precipitating with ethanol (343.0g) addition drop wise at room temperature. The obtained brown amorphous solid was dried under vacuum at 50°C for 2-3 hours. Molecular weight = 261 kDa. Iron content = 22.85 % w/w

Example-5:

Step (i)

16grams of anhydrous iron(III)chloride was dissolved in 50ml of purified water at room temperature for 10 min stirring. The obtained brownish-yellow clear solution was cooled to 0-5°C and the pH was adjusted to 7.0 first by adding aqueous sodium carbonate solution (21gm of Na2CO3dissolved in 102 ml of purified water) and then by adding 20% NaOH solution. A brown colour precipitate obtained was maintained for 1 hour at 0-5°C and collected through filtration (Wet wt. ~54.0g). The cake was suck dried and used for next step.

Step (ii)

20grams of maltodextrin (13-17 dextrose equivalents) were dissolved in 50ml of purified water and the solution was added to a stirred mixture of 2.66gm of Starks catalyst, 0.8gm of Na2WO4.2H2O and 0.37gm of TEMPO at room temperature over a period of 15 minutes. 30gm of H2O2solution was added drop wise over a period of 1 hour at 25-30°C and the temperature was raised to 90-95°C, stirred for 3 hours and cooled to room temperature.

At 25-30°C, wet cake of step (i) added and stirred for 10 minutes. 20% NaOH solution was added drop wise to adjust the reaction mass pH tolO-10.5 and the slurry was heated to 50°C, stirred for 30 minutes. Then the solution was acidified to pH 5.5 with hydrochloric acid addition and the solution was kept at 50°C for another 30 minutes. Further temperature was raised to 95-100°C and stirred for 12 hours. The reaction mixture was allowed to cool to room temperature, adjusted pH to 6.0 to 6.5 with 20% NaOH solution and filtered through a celite pad. Then the iron(III)complex was isolated by precipitating with ethanol (315.0g) addition drop wise at room temperature. The obtained brown amorphous solid was dried under vacuum at 50°C for 2-3 hours. Molecular weight = 236 kDa. Iron content = 22.35 % w/w

Example-6:

Step (i)

20grams of anhydrous ferric chloride was dissolved in 50ml of purified water at room temperature for 10 min stirring. The obtained brownish-yellow clear solution was cooled to 0-5°C and the pH was adjusted to 7.0 by adding 20% NaOH solution. A brown colour precipitate obtained was stirred for 1 hour at 0-5°C and collected through filtration. The cake was suck dried and used for next step.

Step (ii)

20grams of maltodextrin (13-17 dextrose equivalents) were dissolved in 50ml of purified water and the solution was added to a stirred mixture of 2.66gm of Starks catalyst, 0.8gm of Na2WO4.2H2O and 0.37g of TEMPO at room temperature over a

period of 15 minutes. 36gm of H2O2 solution was metered in the course of 1 hour at 25-30°C and the resulting solution was heated to 90-95°C, stirred for 3 hours and cooled to room temperature.

After cooling to 25-30°C, wet cake of step (i) was added and stirred for 10 min. 12ml of 20% NaOH solution was added drop wise to adjust the reaction mass pH to 10-10.5 and the slurry was heated to 50°C, kept at this temperature for 30 minutes. Then the solution was acidified to pH 5.5 with hydrochloric acid addition and the solution was maintained at 50°C for another 30 minutes. Further temperature was raised to 95-100°C and stirred for 12 hours. The reaction mixture was allowed to cool to room temperature, adjusted pH to 6.0 to 6.5 with 20% NaOH solution and filtered through a celite pad. Then the iron(III)complex was isolated by precipitating with ethanol (315.0g) addition at room temperature. The obtained brown amorphous solid was dried under vacuum at 50°C for 2-3 hours. Molecular weight = 365 kDa. Iron content = 23.93 % w/w

Example-7:

20grams of maltodextrin (13-17 dextrose equivalents) were dissolved in 50ml of purified water and the solution was added to a stirred mixture of 2.66gm of Starks catalyst, 0.2gm of Na2WO4.2H2O and 0.37gm of TEMPO at room temperature over a period of 15 minutes. 30gm of H2O2 solution was added drop wise in the course of 1 hour at 25-30°C and the temperature was raised to 90-95°C, stirred for 3 hours and cooled to room temperature.

At 25-30°C, wet cake of step (i) from example-6 was added and stirred for 10 minutes. A pH of 10-10.5 was established by adding 12.0ml of 20% NaOH solution and the slurry was heated to 50°C, stirred at this temperature for 30 minutes. Then the solution was acidified to pH 5.5 with hydrochloric acid addition and the solution was kept at 50°C for another 30 minutes. Further temperature was raised to 95-100°C and stirred for 12 hours. The reaction mixture was allowed to cool to room temperature; pH was adjusted to 6.0 to 6.5 with 20% NaOH solution and filtered through a celite pad. Then the iron(III)complex was isolated by precipitating with ethanol (276.0g) addition drop wise at room temperature. The obtained brown amorphous solid was dried in vacuum at 50°C for 2-3 hours. Molecular weight = 366 kDa. Iron content = 21.2 % w/w

Example-8:

20grams of maltodextrin (13-17 dextrose equivalents) were dissolved in 50ml of purified water and the solution was added to a stirred mixture of 2.66gm of Starks catalyst and 0.8gm of Na2WO4.2H2O at room temperature over a period of 15 minutes. 30grams of H2O2 solution was metered in the course of 1 hour at 25-30°C and the temperature was raised to 90-95°C, stirred for 3 hours and cooled to room temperature.

At 25-30°C, wet cake of step (i) from example-6 was added and stirred for 10 minutes. A pH of 10-10.5 was established by adding 12ml of 20% NaOH solution and the slurry was heated to 50°C, stirred at this temperature for 30 minutes. Then the solution was acidified to pH 5.5 with hydrochloric acid addition and the solution was maintained at 50°C for another 30 minutes. Further temperature was raised to 95-100°C and stirred for 12 hours. The reaction mixture was allowed to cool to 25-30°C, adjusted pH to 6.0 to 6.5 with 20% NaOH solution and filtered through a celite pad. Then the iron(III)complex was isolated by precipitating with ethanol (315.0g) addition drop wise at room temperature. The obtained brown amorphous solid was dried in vacuum at 50°C for 2-3 hours. Molecular weight = 340 kDa. Iron content = 23.28 % w/w

Example-9:

20grams of maltodextrin (13-17 dextrose equivalents) were dissolved in 50ml of purified water and the solution was added to a stirred mixture of 2.66gm of Starks catalyst, 0.8gm of Na2WO4.2H2O and 0.37gm of TEMPO at room temperature over a period of 15 minutes. 30grams of H2O2 solution was added drop wise over a period of 1 hour at 25-30°C and the resulting solution was heated to 90-95°C, stirred for 3 hours and cooled to room temperature.

At 25-30°C, wet cake of step (i) from example- 1 was added and stirred for 10 minutes. A pH of 10-10.5 was established by adding 12ml of 20% NaOH solution and the slurry was heated to 50°C, stirred at this temperature for 30 minutes. Then the solution was acidified to pH 5.5 with hydrochloric acid addition and the solution was maintained at 50°C for another 30 minutes. Further temperature was raised to 95-100°C and stirred for 12 hours. The reaction mixture was allowed to cool to room temperature, adjusted pH to 6.0 to 6.5 with 20% NaOH solution and filtered through a celite pad. Then the iron(III)complex was isolated by precipitating with ethanol (304.0g) addition drop wise at room temperature. The obtained brown amorphous solid was dried under vacuum at 50°C for 2-3 hours. Molecular weight = 352 kDa. Iron content = 23.0 % w/w

Example-10:

20grams of maltodextrin (13-17 dextrose equivalents) were dissolved in 50ml of purified water and the solution was added to a stirred mixture of 2.66gm of Starks catalyst, 0.8gm of Na2WO4.2H2O and 0.37gm of TEMPO at room temperature over a period of 15 minutes. 30grams of H2O2 solution was added drop wise in the course of 60 minutes at 25-30°C and the temperature was raised to 90-95°C, stirred for 3 hours and cooled to room temperature.

At 25-30°C, wet cake of step (i) from example- 1 was added and stirred for 10 minutes. 12ml of 20% NaOH solution was added drop wise to adjust the reaction mixture pH to 10-10.5 and the temperature of the slurry was raised to 50°C, stirred at this temperature for 30 minutes. Then the reaction mixture was acidified to pH 5.5 with hydrochloric acid addition and was maintained at 50°C for another 30 minutes. Further temperature was raised to 95-100°C and stirred for 12 hours. The reaction mixture was allowed to cool to room temperature, adjusted pH to 6.0 to 6.5 with 20% NaOH solution and filtered through a celite pad. Then the iron(III)complex was

isolated by precipitating with ethanol (276.0g) addition drop wise at room temperature. The obtained brown amorphous solid was dried in vacuum at 50°C for 2-3 hours. Molecular weight = 348 kDa. Iron content = 24.6 % w/w