FIELD OF THE INVENTION:
The present invention relates to improved, cost effective process for preparation of water soluble ferric carboxy maltose with reduced impurity suitable for preparation of medicament without involving further purification.
BACKGROUND OF THE INVENTION:
Ferric carboxymaltose is a stable, non-dextran iron complex consisting of ferric hydroxide core stabilized by a carbohydrate shell. Ferric carboxymaltose is commercially available in market under the brand name Ferinject® and is administered intravenously in single doses to treat iron deficiency anaemia.
US2006/0205691 discloses a process for water soluble iron-carbohydrate complexes comprising reacting aqueous solution of iron (III) salt and aqueous solution of one or more oxidation products of maltodextrin. The oxidation of maltodextrin is carried out using aqueous hypochlorite solution at a pH-value within the alkaline range. The drawback of the process is that it involves the use of large amount of toxic ferric chloride and sodium carbonate generating a large quantity of undesired sodium chloride and unacceptable impurities of sodium carbonate resulting in poor quality of iron (III)-carbohydrate complex.
US20120214986 discloses a process for preparation of iron (III) carboxymaltose complex wherein a mixture of one or more maltodextrins, ferric hydroxide and water are heated and the resulting iron maltodextrin complex is oxidized using aqueous sodium hypochlorite solution to yield iron (III) carboxymaltose.
WO2016151367 describes a process for preparation of iron (III) carboxymaltose complex which include reacting aqueous solution of iron (III) salt with aqueous solution of oxidation product of at least one maltodextrin. The oxidation of maltodextrin is carried out in presence of catalyst and phase transfer catalyst in alkaline medium.

The processes in the art require catalysts, phase transfer catalysts for performing oxidation of maltodextrin which add to the manufacturing cost. The use of sodium hypochlorite as the oxidizing agent lead to formation of undesired chlorinated by products. The processes in the art thus suffer from the drawbacks of formation of inorganic impurities such as metal bromides, chlorides and carbonates which impact the yield and purity of iron(III)-carboxymaltose.
The problem to be solved by the present invention is to reduce the impurity formation and provide ferric carboxymaltose which will be suitable for preparation of medicament without involving further purification. Also, the preparation to be provided by the present invention should provide ferric carboxymaltose which is stable, less toxic, avoids dangerous anaphylactic shocks that can be induced by dextran so as to enable a high applicable dosage of ferric carboxymaltose.
The present inventors were of the view that the drawbacks of the prior art processes can be resolved on the basis of oxidation products of maltodextrin using citric acid which functions both as mild oxidizing and cross linking agent. Maltodextrin individually and independently polymerize using citric acid as cross-linkage agent under mild conditions and the resultant polymers obtained are hydrophilic, forming helical inclusion complexes thereby exhibiting larger capability to solubilize in water.
SUMMARY OF THE INVENTION:
In accordance with the above, the present invention provides simple, cost effective
process for preparation of ferric carboxy maltose in good yield and purity
comprising;
i. adding maltodextrin of dextrose equivalent in the range of 10-20 to the suspension of ferric hydroxide with sodium chloride level not more than 45ppm and the chloride content not more than 2.5%w/w;

ii. adding citric acid to the solution of step (i) in an amount of 0.4 to 1.2 equivalent of one aldehyde group per molecule of maltodextrin oxidized followed by heating;
iii. adjusting the pH in the range of 7.0-8.0 using ammonia;
iv. filtering and drying to obtain water soluble ferric carboxy maltose.
DESCRIPTION OF THE INVENTION:
The present invention relates to simple, cost effective process for preparation of
ferric carboxy maltose having mean molecular weight 70,000 to 90,000Da in good
yield and purity. The ferric carboxymaltose obtained by the present process has
iron content of 26% to 35% and is suitable for preparation of medicament without
employing costly Membrane Filtration process using Molecular Weight Cut-off
Membranes.
The present inventors observed that natural α, β and γ Dextrins, Maltodextrin and Dextran can individually and independently polymerize when citric Acid was used as cross-linkage agent under mild conditions. The resultant polymers were hydrophilic, forming helical inclusion complexes thereby exhibiting larger capability to solubilize in water.
Accordingly, the carbohydrate for complex formation with iron was selected from maltodextrin having dextrose equivalent which lies between 10 and 20. The citric acid was used in amount of 0.4 to 1.2 equivalent, preferably of amount 0.6 to 0.8 equivalent of one aldehyde group per molecule of maltodextrin oxidized. The oxidation takes place at the terminal aldehyde group of the maltodextrin. Accordingly, the reactivity caused by glucose content of maltodextrin was lowered to 0.5 % or less. The oxidized maltodextrin polymerizes in presence of citric acid and forms helical inclusion complexes when reacted with iron (III) solutions to obtain water soluble iron-carbohydrate complex.

In an embodiment, the process for preparation of ferric carboxy maltose in good yield and purity is described in detail in the following paras.
Step (i) of the process comprises preparation of ferric hydroxide with reduced impurity levels. Accordingly, to the cooled aqueous ferric chloride solution (38%w/w) was added sodium carbonate solution (20%) slowly with continuous stirring until the pH was in the range of 3.5-4.5. Water was added to the mixture and the solution was allowed to settle for about 7-9 hours. After settling down, the upper layer of the water was decanted and the settled precipitate was filtered and thoroughly washed with water until the sodium chloride content in the rinsed water was not more than 45ppm and the chloride content of ferric hydroxide precipitate was not more than 2.5%w/w. The sodium chloride free ferric hydroxide precipitate was collected and suspension was prepared using water for further reaction.
Step (ii) comprises adding maltodextrin of dextrose equivalent in the range of 10 to 20 slowly to the ferric hydroxide suspension under stirring conditions for complete dissolution. Citric acid was slowly added to the mixture under stirring. The iron-carboxymaltose citric acid complex was heated at 75-80ᵒC for about 8 hours, the reaction mass was cooled to temperature in the range of 35-45ᵒC. Ammonia was then added into the reaction mass to adjust the pH in the range of 7.0-8.0 and allowed to settle.
Step (iii) comprises filtering the solution of the upper layer and drying the clear solution using spray dryer to obtain water soluble ferric carboxymaltose.
The feature of the present invention is that it avoids the contamination of the impurities such as sodium chloride, sodium bromide, organic metal catalyst and excess sodium carbonate in the final complex by providing a substantially pure ferric hydroxide solution for complexing with maltodextrin having dextrose equivalent of 10-20.

The ferric carboxymaltose prepared by the process of the present invention has iron content 26%-35%w/w which can safely be used for preparation of medicament to treat the patients suffering from iron deficiency anaemia.
The invention is further illustrated by means of the following non-limiting examples.
Example 1: Preparation of Ferric hydroxide
Ferric chloride solution (38%w/w; 1315 kg) was added to 600lt of water taken in a reactor and the solution was cooled to 15ᵒC. Sodium carbonate solution (20%w/w) was added slowly to ferric chloride solution under stirring until the pH was 4.0. 3000lt of water was further added to the mixture and the ferric hydroxide precipitate was allowed to settle for 8 hours. Decanted the upper layer of water and the precipitate was transferred to the filter assembly. The ferric hydroxide precipitate was thoroughly washed with water until the sodium chloride in the rinsed water was not more than 45ppm and the chloride content of ferric hydroxide precipitate was not more than 2.5%w/w. Collected the sodium chloride free ferric hydroxide precipitate and water (6000lt) was added to make a suspension in the reactor.
Example 2: Preparation of Ferric carboxymaltose
To the ferric hydroxide suspension (of example 1) in the reactor was added maltodextrin (162 kg) of dextrose equivalent 10-20 slowly under stirring conditions for complete dissolution to obtain a homogeneous solution of maltodextrin. Citric acid (125kg) was added to the solution under stirring and the ferric carboxy maltose citrate complex was heated to a temperature in the range of 75-80ᵒC for 8 hours. Cooled the reaction mass to 40ᵒC. This was followed by addition of ammonia till pH 7.5 was attained. The reaction mass was allowed to settle down for 5 hours and the solution from the upper layer was filtered using suitable filtration assembly. The clear solution after filtration was transferred to the spray dryer. The inlet temperature of the dryer was maintained at 275ᵒC and the outlet temperature at 115ᵒC to obtain dried ferric carboxymaltose.

Yield: 92%
Purity: 96.88%
Iron content: 34.55%
Mol. wt of the complex: 82,000Da
It will be understood that the above description is intended to be illustrative and not restrictive. The embodiments will be apparent to those in the art upon reviewing the above description. The scope of the invention should therefore, be determined not with reference to the above description but should instead be determined by the appended claims along with full scope of equivalents to which such claims are entitled.

1. A simple, cost effective process for preparation of water soluble ferric
carboxy maltose in good yield and purity comprising;
i. adding maltodextrin of dextrose equivalent in the range of 10-20 to the suspension of ferric hydroxide with sodium chloride level not more than 45ppm and the chloride content not more than 2.5%w/w;
ii. adding citric acid to the solution of step (i) in an amount of 0.4 to 1.2 equivalent of one aldehyde group per molecule of maltodextrin oxidized followed by heating to a temperature in the range of 75-80°C;
iii. adjusting the pH in the range of 7.0-8.0 using ammonia;
iv. filtering and drying to obtain water soluble ferric carboxy maltose.
2. The process according to claim 1, wherein the citric acid in step (ii) is used in amount of 0.72 equivalent of one aldehyde group per molecule of maltodextrin oxidized.
3. The process according to claim 1, wherein the mean molecular weight of ferric carboxymaltose is 82,000 Da and the iron content is 34.55%.
4. A pharmaceutical composition for treatment of iron deficiency by parenteral administration comprising stable ferric carboxymaltose prepared by the process of claim 1 along with pharmaceutically acceptable excipients.
5. A method for treatment of iron deficiency comprising administering the parenteral composition of ferric carboxymaltose prepared by the process of claim 1 along with pharmaceutically acceptable excipients.