Field of the Invention:

The present invention relates to novel polymorphic forms of rosuvastatin calcium and its use in the preparation of pharmaceutical composition. Rosuvastatin calcium is chemically known as bis[(E)-7-[4-(4-fluorophenyl)-6-iso-propyl-2-[methyl (methyl sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium and is represented by the following structural formula-1

Formula-1
Rosuvastatin calcium is commercially available under the brand name of Crestor® for the treatment of high cholesterol and related conditions, and to prevent cardiovascular disease, marketed by AstraZeneca. The active ingredient of crestor i.e., rosuvastatin calcium is present in amorphous form.

Background of the Invention:

Rosuvastatin, its pharmaceutically acceptable salts, especially calcium salt and process for its preparation have been disclosed in US 5260440. The disclosed process involves the dissolution of rosuvastatin sodium salt in water, adding calcium chloride and isolating the resultant precipitate by filtration then drying it to get calcium salt of rosuvastatin. Rosuvastatin calcium obtained as per this process is an amorphous powder and having water content about 2-5%.

According to US patent US 6548513, the particular problem associated with rosuvastatin calcium is that it undergoes degradation under certain conditions. The major degradation products formed are the corresponding (3R,5S) lactone and an oxidation product in which the hydroxyl group adjacent to the carbon-carbon double bond is oxidized to a ketone functionality.

The potential for degradation of rosuvastatin calcium makes it difficult to formulate it and provide pharmaceutical composition with long storage life for the marketed product. Hence it is necessary to have a stable amorphous form of rosuvastatin calcium which does not undergo any degradation during storage and packing.

International publication WO 00/42024 disclosed a crystalline form A of rosuvastatin calcium, which is prepared by dissolving the amorphous rosuvastatin calcium in a mixture of water and an organic solvent such as acetone or acetonitrile under heating then cooling the obtained reaction mixture to get the crystalline form A of rosuvastatin calcium.

International publication WO 05/023779 disclosed hydrated crystalline form-B and anhydrous crystalline form-B 1 rosuvastatin calcium. Form B is prepared by dissolving the amorphous form in water and where as form-B 1 is prepared by removing water from the crystal lattice of form-B.

International publication WO 06/079611 disclosed crystalline form-B and form-C rosuvastatin calcium. The said crystalline forms are prepared by dissolving the amorphous rosuvastatin in a mixture of water and an anionic surfactant such as alkyl sulphates or dissolving the amorphous form in a mixture of water and organic solvent under heating and then cooling the obtained solution to precipitate crystalline form B or form C.

Crystalline forms often show different physical and/or biological characteristics which may assist in the manufacture or formulation of the active compound, with the purity levels and uniformity required for regulatory approval. Crystalline forms of such active compounds may also possess improved pharmacological characteristics, for example, improved bioavailability, and therefore, novel crystalline forms offer enhanced possibilities to modulate and design improved drug products. Therefore there exists a need for crystal forms other than those prior reported forms of rosuvastatin calcium which have the desired and the required biological qualities which would be helpful in optimizing, manufacturing and formulating an effective pharmaceutical composition.

Brief Description the Invention:

The first aspect of the present invention provides a novel crystalline form-M of rosuvastatin calcium and hydrates thereof.
The second aspect of the present invention is to provide a process for the preparation of novel crystalline form-M of rosuvastatin calcium and hydrates thereof
The third aspect of the present invention is to provide amorphous form of stable rosuvastatin calcium having enhanced stability w.r.to 5-oxo impurity during storage and formulation and also use of the same in the preparation of pharmaceutical composition.

The fourth aspect of the present invention is to provide a process for the preparation of stable amorphous rosuvastatin calcium having water content of 5-9% w/w.
Brief description of the Figures:

Figure-1: Illustrates PXRD of crystalline form-M of Rosuvastatin calcium salt. Flgure-II: Illustrates DSC of crystalline form-M of Rosuvastatin calcium salt.
Detailed Description of the Invention:
As used herein the term "5-oxo impurity" refers to the degradation impurity chemically known as 7-[4-(4-fluorophenyl)-6-isoproyl-2-[methyl(methylsulfonyl) amino]pyrimidin-5 -yl] -3 -hydroxy- 5 -oxo-hept-6-enoic acid.
The first aspect of the present invention provides a novel crystalline form of rosuvastatin calcium, which is characterized by its powder X-ray powder diffraction pattern showing characteristic peaks at 3.33, 5.30, 7.52 and 22.46 ±0.2 degrees 20. This crystalline form of rosuvastatin calcium is hereinafter designated as crystalline form-M. The crystalline form-M of the present invention further characterized by its PXRD showing peaks at 10.37 and 20.45 ±0.2 degrees 29. The PXRD of crystalline form-M is substantially similar to the PXRD pattern depicted in figure-1.
Further the crystalline form-M of the rosuvastatin calcium is characterized by its DSC thermo gram. The DSC having an endotherm at about 103.3°C and another endotherm at about 175.7°C. The DSC of crystalline form-M of rosuvastatin calcium is depicted in Figure-II.
The second aspect of the present invention provides a process for the preparation of crystalline form-M of rosuvastatin calcium, which comprises of
a) Taking the amorphous rosuvastatin calcium in mixture of ketone solvent and water,
b) warming the mixture to obtain a clear solution,
c) cooling the reaction mixture to ambient temperature and stirring for 15-20 hours,
d) filtering the precipitated solid,
e) drying the solid compound under aerial conditions to provide the crystalline form.
Wherein in step a) the ketone solvent used is selected fi-om acetone or methyl isobutyl ketone; the ratio of water is in amount of about 2 volumes to about 15 volumes preferably 10 volumes to the weight of the compound. The amount of ketone solvent taken is about 2 volumes to about 15 volumes, preferably 10 volumes to the weight of the compound taken. In step b) the temperature to which the mixture is heated is in the range of 25°C to 50°C, preferably 41°C and in step c) ambient temperature refers to the temperature in the range of 25°C to 28°C.

The third aspect of the present invention provides amorphous rosuvastatin calcium having water content of 5 to 9%, preferably 6-8% w/w. The amorphous rosuvastatin calcium having 6-8% of water content of present invention having enhanced stability with respect to 5-oxo impurity during the storage and formulation of the same. The stability of amorphous rosuvastatin calcium of the present invention is further characterized by it contains 0.01% of 5-oxo impurity after HPLC after subjected to the stability testing at 25±2°C and 60 ± 5% relative humidity for 6 months.

A process for the preparation of stable amorphous rosuvastatin calcium containing water content of 6-8% of the present invention, comprises of the following steps,
a) Slurrying the amorphous rosuvastatin calcium in water at 25-30°C,
b) filtering the reaction mixture and washing with water.
c) aerial drying the obtained compound until the water content of rosuvastatin calcium reaches 6-8% w/w.

Further the present invention provides a process for the preparation of stable amorphous rosuvastatin calcium having water content of 6-8%w/w, which comprises of the following steps,
a) Treating the methylamine or tertiarybutylamine salt of rosuvastatin with aqueous sodium hydroxide to provide rosuvastatin sodium,
b) setting the reaction mixture pH to 9.0 to 9.2 by evaporating the solvent containing the corresponding amine under nitrogen atmosphere followed by extracting the reaction mixture with tertiary butyl acetate to remove corresponding organic amine,
c) water was added to the aqueous reaction mixture,
d) adding aqueous calcium acetate solution to the above aqueous reaction mixture at 25- 29°C,
e) stirring the reaction mixture at 25-29°C,
f) filtering the solid and washing with water,
g) drying the solid at 25-30°C until the water content reaches to 6-9% to get the stable amorphous rosuvastatin calcium.
Rosuvastatin calcium prepared by the prior art processes and prior art pharmaceutical composition containing the rosuvastatin calcium were known to have a water content of about 2-5%. 5-oxo impurity level found to be enhanced in the rosuvastatin calcium having water content of 3-6%. When this rosuvastatin calcium is used in the formulation there an enhancement of 5-oxo impurity during storage. In order to enhance the stability and control the degradation products specific stabilizing agent is required in pharmaceutical composition. For example, US 6548513 involve the usage of tribasic calcium phosphate as a stabilizing agent to control the enhancement of 5-oxo impurity.

We the present inventors while working to resolve this problem in API itself, found that by increasing the water content of amorphous rosuvastatin calcium enhance the stability of the material with respect to 5-oxo impurity. Hence rosuvastatin calcium samples with different levels of water content were prepared and analyzed by HPLC & PXRD techniques. It was surprisingly foimd that the amorphous rosuvastatin calcium having water content greater than 6% having enhanced stability with respect to 5-oxo impurity than amorphous rosuvastatin calcium having water content less than 5%. During this study and analysis at different intervals of time and we found that sample having water content 6-8% is more stable, further enhancement of 5-oxo-impurity has not been observed. There is no change in the amorphous nature of the rosuvastatin calcium which has been confirmed by PXRD. Also the stability study shows that the possibility of enhancement of 5-oxo impurity is more in rosuvastatin calcium having water content less than 6%. The same has been further confirmed by the following stability details of amorphous rosuvastatin calcium having water content of 1-5% w/w & stability details of amorphous rosuvastatin calcium of the present invention having water content of 5 to 11 % with respect to 5-oxo impurity.
Table-1: Stability details of amorphous rosuvastatin calcium having water content of 1-5% w/w with respect to 5-oxo impurity
Water Stability at different intervals
content of 5-Qxo impurity Leve (%)
Batch Number Rosuvastatin st
calcium in Initial o/o (w/w) month month
1 09 006 L79 4.22
2 U 006 2,48 5.68
3 L7 L28 L42 1.80
4 Z26 004 L29 1.61
5 328 003 027 0.42
6 4.83 0.03 0.17 0.28
Table-2: Stability details of amorphous rosuvastatin calcium of the present invention having water content of 5-11% w/w with respect to 5-oxo impurity
Water Stability at different intervals
Batch content of 5-Oxo impurity Leve (%)
T.T , Rosuvastatin Tst Tiin
Number ... ^ . . . 1 2
calcium m Initial o/o (w/w) month month
1 106 003 005 0.08
2 5.88 0.03 0.04 0.06
3 5.98 0.03 0.03 0.04
4 6,10 OOl OOl 0.01
5 6,62 OOl OOl 0.01
6 730 N/D N/D N/D
7 7,80 N/D N/D N/D
8 8,90 N/D N/D N/D
9 9,10 N/D N/D N/D
10 11.0 I N/D I N/D I N/D
N/D- refers to the impurity present in the non-detectable level.
Further the stable amorphous rosuvastatin calcium containing 6-8% of water can be used in the preparation of stable pharmaceutical composition. The pharmaceutical composition can be prepared by the methods known in the art. As there is no increase in amount of 5-oxo impurity found in API, it may not enhance in the composition containing the same. Hence the pharmaceutical composition containing the stable amorphous rosuvastatin calcium of the present invention having enhanced stability w.r.to 5-0X0 impurity can be formulated.

PXRD analysis of rosuvastatin calcium were carried out using SIEMENS/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.0457min. The thermal analysis of rosuvastatin calcium was carried out on Waters DSC Q-10 model differential scanning calorimeter.

5-0X0 impurity in rosuvastatin calcium was analyzed by HPLC using the following conditions: A liquid chromatograph is equipped with variable wavelength UV detector or PDA detector; Column: Phenomenex, CI8, 250 x 4.6 mm, 5.0 |im or equivalnet; wavelength: 248 nm ; Temperature: 25°C; Load: 20 |j,1; Run time: 70 min; and using a mixture of acetonitrile and water in the ration of 1:1 as a diluent and mixture of water:acetonitirle:methanoI:triethyIamine as a mobile phase.

The present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:
Example-1: Preparation of crystalline Form-M of rosuvastatin calcium:
To 50 grams of amorphous rosuvastatin calcium salt added a mixture of water (550 ml) and acetone (550 ml) at 27°C. The reaction mixture was heated to 40°C and then slowly cooled to 27°C. Stirred the reaction mixture for 20 hrs at the same temperature. Filtered the precipitated product and dried under aerial conditions to get the form-M of rosuvastatin calcium. Yield: 31 grams

Example-2: Preparation of crystalline Form-M of rosuvastatin calcium:
To 50 grams of amorphous rosuvastatin calcium salt added a mixture of water (500 ml) and methylisobutylketone (500 ml) at 27°C. The reaction mixture was heated to 40°C and then slowly cooled to 27°C. Stirred the reaction mixture for 20 hrs at the same temperature. Filtered the precipitated product and dried under aerial conditions to get the form-M of rosuvastatin calcium. Yield: 32.6 grams
Exmaple-3: Preparation of stable amorphous rosuvastatin calcium:
Water (50 ml) was added to a amorphous rosuvastatin calcium (10 grams) at 25-30°C. The reaction mixture was stirred for 30 minutes at 25-30°C. Filtered the solid, washed with water and then dried under aerial condition up to the water content of 6-8%. Yield: 9.2 grams Water content: 6.8 %

Purity by HPLC: 99.68% 5-oxo impurity: Not detected
Example-4: Preparation of stable amorphous rosuvastatin calcium:
Aqueous sodium hydroxide (9 grams in 110 ml water) was added to a mixture of tertiarybutylamine salt of rosuvastatin (125 grams) and water (630 ml) at 20-3 0°C and stirred for 1.5 hours. The reaction mixture was washed with tertiary butyl acetate and the reaction mixture was expelled with nitrogen until the pH reaches 9.1 at 40°C. The reaction mixture was cooled to 25-29°C and filtered through micron filter and washed with water. Aqueous calcium acetate (21.4 grams in 125 ml of water) solution was added to the filtrate at 25-29°C and stirred for 45 minutes at 25-29°C. The obtained solid was filtered, washed with water and then dried at 25-30°C until the water content reaches 6- 9% w/w to get the title compound. Yield: 112 grams
Purity by HPLC: 99.74%; 5-oxo impurity: Not detected Water content: 7.2% w/w
Example-5: Preparation of stable amorphous rosuvastatin calcium:

Aqueous sodium hydroxide (8 grams in 110 ml water) was added to a mixture of methylamine salt of rosuvastatin (125 grams) and water (630 ml) at 20-30°C and stirred for 1.5 hours. The reaction mixture was washed with tertiary butyl acetate and the reaction mixture was expelled with nitrogen until the pH reaches 9.2 at 40°C. The reaction mixture was cooled to 25-29°C and filtered through micron filter and washed with water. Aqueous calcium acetate (21.4 grams in 125 ml of water) solution was added to the filtrate at 25-29°C and stirred for 45 minutes at 25-29°C. The obtained solid was filtered, washed with water and then dried the material at 25-30°C until the water content reaches 6-9% w/w. Yield: 110 grams
Purity by HPLC: 99.71%; 5-oxo impurity: Not detected Water content: 7.9% w/w

We Claim:
1. Amorphous rosuvastatin calcium having water content of 5-9% w/w, preferably 7-8% w/w.

2. Amorphous rosuvastatin calcium of claim 1 is substantially free of 5-oxo impurity.

3. Stable amorphous rosuvastatin calcium having water content of 6-8% w/w, characterized in that it contains 5-oxo impurity in the level of less than 0.01% by HPLC after subjected to the stability testing at 25±2°C and 60 ± 5% relative humidity for 6 months.

4. A process for the preparation of stable amorphous rosuvastatin calcium of claim-1, comprises of
a) Slurring the amorphous rosuvastatin calcium in water,
b) filtering the reaction mixture washing with water, and
c) aerial drying of the obtained compound till the water content reaches upto 6-8% w/w to get the stable amorphous rosuvastatin calcium.

5. Use of amorphous rosuvastatin calcium of any preceeding claims in the preparation of pharmaceutical composition.

6. A pharmaceutical composition comprising rosuvastain calcium containing 6-8% of water as claimed in claim 1 to 3 to have enhanced stability with respect to 5-Oxo impurity.

7. A novel crystalline form-M of rosuvastatin calcium characterized by its X-ray powder diffraction pattern shows peaks at 3.33, 5.30, 7.52 and 22.46 ± 0.2 degrees 29.

8. A novel crystalline form-M of rosuvastatin calcium of claim 8 further characterized by its PXRD shown peaks at 10.37 and 20.45 ± 0.2 degrees 20.

9. A novel crystalline form M of rosuvastatin calcium of claim 7 or 8 is further characterized by its DSC thermogram showing endotherm at about 103.3°C and another endotherm at about 175.7°C.

10. A process for the preparation of novel crystalline form-M of rosuvastatin calcium comprises of the following steps,

a) Taking the amorphous rosuvastatin calcium in a mixture of ketone solvent and water,
b) warming the mixture to obtain a clear solution,
c) cooling the reaction mixture to ambient temperature and stirring for 15-20 hours,
d) filtering the precipitated solid,
e) drying the solid compound under aerial conditions to provide the crystalline form.