DESC:DESCRIPTION OF THE RELATED ART
Ferumoxytol is disclosed in U.S Patent No. 6,599,498. Ferumoxytol (Polysaccharide superparamagnetic iron oxide) is a nanoparticle formed by encapsulating superparamagnetic iron oxide with polydextrose sorbitol carboxymethyl ether. The injection of this drug was approved by the FDA in 2009 for the treatment of chronic kidney disease (CKD). Iron deficiency anemia in adult patients. The overall colloidal particle size is 17-31 nm in diameter. The chemical formula of Feraheme is Fe5874O8752-C11719H18682O9933Na414 with an apparent molecular weight of 750 kDa.

Controlling of Bacterial endotoxins (BET) is very much important in injections. Endotoxin is a component in the cell wall of Gram-negative bacteria called lipopolysaccharide. Lipopolysaccharide is toxic to the host. Common methods of endotoxin removal include high concentration acid-base removal method, ultrafiltration membrane and charged microporous membrane method, asbestos and activated carbon adsorption method, chemical degradation method, ion exchange chromatography, affinity chromatography. The polysaccharide superparamagnetic iron oxide bulk drug contains a large amount of free sugars, and the pH is neutral, which is very suitable for the growth of microorganisms, and the endotoxin is extremely difficult to control.
Present invention provides solid Ferumoxytol which has below BET level.

OBJECT OF THE INVENTION
The main object of the present invention is to provide solid Ferumoxytol and its process for the preparation thereof.

SUMMARY OF THE INVENTION
In one aspect, the present invention provides solid Ferumoxytol.

In one embodiment, present invention provides a process for the preparation of solid Ferumoxytol, comprising the steps of:
a) treating Ferumoxytol solution in water miscible organic solvent; and
b) isolating solid Ferumoxytol.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that the description of the present invention has been simplified to illustrate elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that may be well known.

The main aspect of the present invention provides solid Ferumoxytol.

In one embodiment present invention provides a process for the preparation of solid Ferumoxytol, comprising the steps of:
a) treating Ferumoxytol solution with water miscible organic solvent; and
b) isolating solid Ferumoxytol.

Within the context of the present embodiment, Ferumoxytol solution is mixed with water miscible organic solvent at a temperature of 45°C to 60°C. In particularly useful embodiments, Ferumoxytol solution is mixed with water miscible organic solvent at a temperature of 50°C to 60°C. The reaction mass is stirred for 1-5 hours and cooled to a temperature of 25°C to 45°C. In particularly useful embodiments, the reaction mass is cooled to 42±3°C. In particularly useful embodiments, water miscible organic solvent is selected from but not limited to alcohols such as methanol, ethanol, isopropanol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; Nitriles such as acetonitrile. Preferably alcohol is used, more preferably ethanol is used.

Isolation of Ferumoxytol may be carried out by methods well-known and often used in the art, for example, by filtering the mixture to obtain a solid.

In another embodiment, present invention provides process for the preparation of input Ferumoxytol solution which is used to prepare solid Ferumoxytol comprising the steps of;
a) suspending Carboxymethyl reduced dextran in water;
b) cooling the reaction mass at a temperature of 5°C to 15°C;
c) adding Ferric chloride hexahydrate solution and Ferrous chloride solution to step (b);
d) adding Ammonium chloride solution to the reaction mass;
e) adding sodium hydroxide solution;
f) raising the reaction mass temperature 75°C to 95°C and maintaining the reaction mass at same temperature for 10 to 30 hours;
g) cooling the reaction mass at a temperature of 20°C to 35°C;
h) filtering the reaction mass;
i) adjusting pH of reaction mass to 7.4 to 8.2;
j) concentrating the reaction mass by ultra-filtration (Dia-filtration);
k) diluting the reaction mass obtained in step (j), with water; and
l) repeating the step (j).

Within the context of the present embodiment, Carboxymethyl reduced dextran is suspended in water, cooled the reaction mass at a temperature of 5°C to 15°C. In particularly useful embodiments, reaction mass was cooled to a temperature of 10±2°C. Ferric chloride hexahydrate solution and Ferrous chloride solutions were added to the obtained reaction mass.
Ammonium chloride solution was added to the reaction mass followed by Sodium hydroxide solution. Reaction temperature was raised to 75-95°C and maintained at same temperature for 10 to 30 hours. The quantity of ammonium hydroxide is very important for getting required molecular weight of the Ferumoxytol complex. Due to easily vaporization of ammonia during its handling, analysis leads to give inconsistent result of Ferumoxytol. To overcome this problem, it was surprisingly found that when Ammonium hydroxide is generated in-situ using ammonium chloride and sodium hydroxide and hence there is control on ammonia therefore it gives reproducible results.
After the above step, reaction temperature was raised to 80-85°C and maintained at same temperature for 18-23 hours. Reaction was cooled to 20-35°C. In particular useful embodiments, reaction mass temperature was cooled to 25-28°C. The obtained reaction mass pH was adjusted to 7.4 to 8.2 using sodium hydroxide solution. The reaction mass was filtered using ultrafiltration through 100kDa membrane by diluting the reaction mass with water for 2 to 6 times. The obtained reaction mass can be further concentrated with distillation method to get Ferumoxytol solution. In particularly useful embodiments this concentrated Ferumoxytol is used as input material to prepare solid Ferumoxytol.
Advantages of the present invention:
Ferumoxytol is an injection solution with Iron content is around 30 mg / ml. Since it is an injection, control of Bacterial endotoxins (BET) is very much important. Literature processes indicates that the final solution after ultrafiltration is considered as an API and it is stored at around 4°C to avoid microbial growth. Since the literature process involves multiple ultrafiltration, the Bacterial endotoxins are accumulated in the solution and it is very difficult to obtain BET level below 0.5 EU/ ml. Isolation of Solid Ferumoxytol using organic solvents such as ethanol ensures the removal of BET from API and gives BET level to below 0.2 EU / ml.
Handling and storage of solid Ferumoxytol material is easy, and it can be stored at room temperature and whenever the injection solution is to be prepared, solid material can be dissolved in WFI water and used as an API.

Example:
45 g of Carboxymethyl reduced dextran (water content around 16%) is added to the flask along with 1000ml of WFI (water for injection) water and nitrogen purging is initiated. pH of solution is adjusted to 10.0 with 1% NaOH solution. Reaction mass is filtered through micron and washed with 127ml of WFI water. It is then cooled to 10±2°C under continuous nitrogen purging through solution and 57.3 g of Ferric chloride hexahydrate solution (assay around 26.7%) is added to it followed by 200ml of WFI water. 31.4 g of Ferrous chloride solution (assay around 31.8%) is added to the reaction mass followed by 200ml WFI water. Reaction mass is stirred for 30 minutes and Ammonium chloride solution (23.7g ammonium chloride dissolved in 80ml of WFI water) is added to the reaction mass followed by Sodium hydroxide solution (17.3g of Sodium hydroxide dissolved in 80 ml WFI water) and rinsing with 20 ml of WFI water. Gradually reaction mass temperature is raised to 25±3°C and then to 50±3°C. It is then stirred for 30 minutes at 50±3°C and then further raised to 83±2°C. Reaction mass temperature is maintained at 83±2°C for 20 hours with continuous nitrogen purging through the reaction mass. Reaction mass is cooled to 27±3°C and filtered through hyflo bed and washed with 200ml of WFI water. pH of the filtrate is adjusted to 7.4 to 8.2 using sodium hydroxide solution. Reaction mass is filtered through micron, and it is subjected to ultrafiltration through 100kDa membrane filtration to bring down volume to around 260 ml. It is further diluted with 300ml of WFI water and concentrated to around 260ml with ultrafiltration. The cycle is further repeated for another 2 times. Reaction mass is further concentrated to around 95ml under vacuum distillation at below 65°C. Temperature of reaction mass is adjusted to 53±3°C and 500 ml Ethanol is added slowly to it and stirred for 2 hours. It is then cooled to 42±3°C and filtered off and washed with 100 ml of Ethanol. It is dried under vacuum at 55-60°C to obtain 20-24g of solid Ferumoxytol.
,CLAIMS:
1. Solid Ferumoxytol.
2. A process for the preparation of solid Ferumoxytol, comprising the steps of:
a) treating Ferumoxytol solution with water miscible organic solvent; and
b) isolating solid Ferumoxytol.
3. The process as claimed in claim 2, wherein the organic solvent is selected from methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone and acetonitrile.
4. A process for the preparation of input Ferumoxytol solution which is used to prepare solid Ferumoxytol comprising the steps of;
a) suspending Carboxymethyl reduced dextran in water;
b) cooling the reaction mass at a temperature of 5°C to 15°C;
c) adding Ferric chloride hexahydrate solution and Ferrous chloride solution to step (b);
d) adding Ammonium chloride solution to the reaction mass;
e) adding sodium hydroxide solution;
f) raising the reaction mass temperature 75°C to 95°C and maintaining the reaction mass at same temperature for 10 to 30 hours;
g) cooling the reaction mass at a temperature of 20°C to 35°C;
h) filtering the reaction mass;
i) adjusting pH of reaction mass to 7.4 to 8.2;
j) concentrating the reaction mass by ultra-filtration (Dia-filtration);
k) diluting the reaction mass obtained in step (j), with water; and
l) repeating the step (j).