DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. 2127/CHE/2014 filed on April 25, 2014.

BACKGROUND OF THE INVENTION

FIELD OF THE DISCLOSURE
The present disclosure provides an improved process for the preparation of crystalline levomefolate calcium Form C.
DESCRIPTION OF THE RELATED ART
Levomefolate calcium is dietary supplement, which is therapeutic agent for the treatment of megaloblastic folic acid deficiency anemia, as an antidote for increasing the compatibility of folic acid antagonists, particularly of aminopterin and methotrexate in cancer chemotherapy.

Levomefolate calcium is chemically known as N-[4-[[(2-amino-1,4,5,6,7,8-hexahydro-5-methyl-4-oxo-(6S)-pteridinyl)methyl]amino]benzoyl]-L-glutamic acid calcium salt, having the below structure.

Levomefolate and pharmaceutically acceptable salts are first disclosed in G.B Patent No. 1,572,137, this patent does not discuss about polymorphic forms. U.S. Patent No. 5,124,452 and U.S. Patent No. 5,223,500 disclosed pentahydrate and amorphous forms of levomefolate calcium.

U.S. Patent No. 5,350,850 discloses a process for the preparation of levomefolate calcium, wherein an aqueous solution of folic acid is hydrogenated with a high stoichiometric excess of sodium borohydride and catalytic amount of ethylenediaminetetraacetic acid (EDTA), treating with formaldehyde, followed by sodium borohydride to obtain levomefolate calcium.

U.S. Patent No. 5,457,202 discloses a process for the resolution of (6R,S)-5-methyltetrahydrofolic acid comprising, N-ethyl-2-aminomethylpyrrolidine were added to (6R,S)-5-methyltetrahydrofolic acid in water. The reaction mixture was heated to dissolve 6S-acid isomer; the undissolved 6R-acid is filtered. The filtrate was cooled to 20 °C to precipitate 6S-acid isomer and the crystals were filtered to obtain N-ethyl-2-aminomethylpyrrolidine salt of (6S)-5-methyltetrahydrofolic acid. The suspension of the above salt is taken in water; calcium chloride is added to form levomefolate calcium.

U.S. Patent No. 6,441,168 discloses four crystalline modifications of levomefolate calcium namely Type-I, Type-II, Type-III and Type-IV. This patent also discloses amorphous levomefolate calcium, wherein levomefolate is treated with calcium chloride in water, the obtained solid is filtered at 25-35 °C and dried under vacuum at 45 °C to get amorphous product.

PCT Publication No. WO2008144953A1, discloses a process for the preparation of amorphous levomefolate calcium, wherein levomefolate calcium is crystallized from aqueous ethanol to obtain amorphous levomefolate calcium.

PCT Publication No. WO2013107236A1, discloses crystalline levomefolate calcium Form C. This patent publication also discloses a process for the preparation of crystalline levomefolate calcium Form C, wherein levomefolate calcium is crystallized from a polar medium in ultrasonic reactor.

The present disclosure provides an improved process for the preparation of crystalline levomefolate calcium Form C, which is feasible in large scale production with high purity.

SUMMARY OF THE DISCLOSURE

The main aspect of the present disclosure is to provide an improved process for the preparation of crystalline levomefolate calcium Form C.

One aspect of the present disclosure is to provide an improved process for the preparation of crystalline levomefolate calcium Form C comprising the steps of;
a) dissolving amorphous levomefolate calcium in water at elevated temperature;
b) stirring the solution at same temperature;
c) cooling the resulting solution to ambient temperature; and
d) filtering to get crystalline Form C of levomefolate calcium

DETAILED DESCRIPTION OF THE DISCLOSURE

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 present invention is directed to an improved process for the preparation of crystalline levomefolate calcium Form C.

One embodiment of the present disclosure is to provide an improved process for the preparation of crystalline levomefolate calcium Form C comprising the steps of;
a) dissolving amorphous levomefolate calcium in water at elevated temperature;
b) stirring the solution at same temperature;
c) cooling the resulting solution to ambient temperature; and
d) filtering to get crystalline levomefolate calcium Form C.

According to the present disclosure, amorphous levomefolate calcium is dissolved in water at elevated temperature, stirred the solution at same temperature to get complete material precipitation; cooled the solution to ambient temperature under stirring and filtered the solution to get crystalline levomefolate calcium Form C. The obtained crystalline levomefolate calcium Form C is dried under vacuum at 30-40 °C.

Within the context of the present disclosure, elevated temperature ranges from 60-90 °C, preferably 65-75 °C and ambient temperature ranges from 20-40 °C, preferably 25-35 °C.

According to the present disclosure amorphous levomefolate calcium is dissolved in water at 65-75 °C; stirred the solution at the same temperature for 1-5 hours; cooled the solution to 25-35 °C under stirring; filtered the solution, washed with water and suck dried to get crystalline Form C of levomefolate calcium; the obtained product was further dried under vacuum at 30-40 °C.

According to the present disclosure the input amorphous levomefolate calcium is prepared by prior-art methods.

Yet another embodiment of the present disclosure, below compounds are identified as possible impurities of levomefolate.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present application. While particular aspects of the present application have been illustrated and described, it would be apparent to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the disclosure. It is therefore intended to encompass all such changes and modifications that are within the scope of this disclosure.

Example: 1
Preparation of crystalline Form C of levomefolate calcium.
Levomefolate calcium (5 g) was suspended in hot water at 65-70 °C (50 mL) under nitrogen atmosphere. The solution was stirred at 65-75 °C for 1-2 hours to get complete material precipitation, and then cooled to 25-35 °C. The material was recovered from filtration and washed with water (20 mL), further dried under vacuum at 30-35 °C.
Yield: 0.6
Water content: 14.61%w/w
HPLC Purity: 98.97%

Example: 2
Preparation of crystalline Form C of levomefolate calcium.
Levomefolate calcium (5 g) was suspended in hot water at 65-70 °C (50 mL) under nitrogen atmosphere. The solution was stirred at 65-75 °C for 5 minutes. Then settled the solution to get complete material precipitation, and then cooled to 25-35 °C under stirring. The material was recovered from filtration and washed with water (10 mL), further dried under vacuum at 40 °C.
Yield: 0.63
Water content: 13.73%w/w
HPLC Purity: 98.91%

Example: 3
Preparation of crystalline Form C of levomefolate calcium.
Levomefolate calcium (5 g) was suspended in hot water at 65-70 °C (50 mL) under nitrogen atmosphere. The solution was stirred at 65-75 °C for 60 minutes with high RPM. Then cooled to 25-35 °C under stirring. The material was recovered from filtration and washed with water (10 mL), further dried under vacuum at 40 °C.
Yield: 0.54.
Water content: 13.45%w/w
HPLC Purity: 99.03%

Example: 4
Preparation of crystalline Form C of levomefolate calcium.
Levomefolate calcium (5 g) was suspended in hot water at 65-70 °C (50 mL) under nitrogen atmosphere. The solution was stirred at 65-75 °C for 5 hours. The reaction mass cooled to 25-35 °C under stirring. The material was recovered from filtration and washed with water (10 mL), further dried under vacuum at 40 °C.
Yield: 0.64
Water content: 14.48%w/w
HPLC Purity: 97.27%

Example: 5
Preparation of crystalline Form C of levomefolate calcium.
Levomefolate calcium (5 g) was suspended in hot water at 65-70 °C (50 mL) under nitrogen atmosphere. The solution was stirred at 65-75 °C for 5 hours. The material was recovered from filtration at same temperature and washed with water (10 mL), further dried under vacuum at 40 °C.
Yield: 0.64
Water content: 14.84%w/w
HPLC Purity: 97.15%

Example: 6
Preparation of crystalline Form C of levomefolate calcium.
Levomefolate calcium (5 g) was suspended in hot water and methanol 1:1 ratio at 65-75 °C (50 mL) under nitrogen atmosphere. The solution was stirred at 65-75 °C for 1 hour. The reaction mass cool to 25-35 °C under stirring. The material was recovered from filtration and washed with water (10 mL), further dried under vacuum at 35 °C.
Yield: 0.78
Water content: 13.42%w/w
HPLC Purity: 98.72%

Example: 7
Preparation of crystalline Form C of levomefolate calcium.
Levomefolate calcium (5 g) was suspended in hot water at 90 °C (50 mL) under nitrogen atmosphere. The solution was stirred at 90 °C for 1 hour. The material was recovered from filtration at same temperature and washed with water (20 mL), further dried under vacuum at 35 °C.
Yield: 0.74
Water content: 13.06%w/w
HPLC Purity: 99.19%

CLAIMS:1. An improved process for the preparation of crystalline levomefolate calcium Form C comprising the steps of:
a) dissolving amorphous levomefolate calcium in water at elevated temperature;
b) stirring the solution at same temperature;
c) cooling the resulting solution to ambient temperature; and
d) filtering to get crystalline levomefolate calcium Form C.

2. The process according to claim 1, wherein the elevated temperature ranges from 60-90 °C.

3. The process according to claim 1, wherein the ambient temperature in step (b) ranges from 20-40 °C.