FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"A NOVEL CRYSTALLINE FORM OF ROSUVASTATIN CALCIUM"
Enaltec Labs Pvt Ltd. an Indian Company, having its Registered office at 17th Floor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India, pin Code- 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

A NOVEL CRYSTALLINE FORM OF ROSUVASTATIN CALCIUM
FIELD OF THE INVENTION:
The present invention relate to a novel crystalline form of rosuvastatin calcium hereinafter designated as Form E as well as processes for its manufacture and pharmaceutical composition comprising rosuvastatin crystalline Form E, which is useful as an agent for treating hyperlipidemia, hypercholesterolemia and atherosclerosis.
BACKGROUND OF THE INVENTION:
The chemical name of rosuvastatin calcium is bis [(E)-7-[4(4-fluorophenyl)-6-isopropyl-2-[N-methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S) -3, 5- dihydroxyhept-6-enoic acid] calcium salt and is known from U.S. Patent No. 5, 260, 440 and is represented by structural formula I.

Formula I
Rosuvastatin calcium is commercially available under the brand name of CRESTOR in USA and is marketed by Astrazeneca.
Rosuvastatin calcium is indicated and usage for hyperlipidemia; mixed dyslipidemia; hypertriglyceridemia; primary dysbetalipoproteinemia (type III hyperlipoproteinema);

homozygous familial hypercholesterolemia; slowing of the progression of atherosclerosis and primary prevention of cardiovascular disease.
Rosuvastatin calcium obtained by following the process disclosed in U.S. Patent No. 5, 260, 440 is in amorphous form.
U.S. Patent no. 6,589,959 discloses a crystalline form of rosuvastatin calcium and hydrates thereof, designated as form A.
U.S. Patent Publication No. 2010/0222373 discloses crystalline hydrated form of rosuvastain calcium, designated as form B, and the rosuvastatin calcium dehydrated form, designated as form B-1.
U.S. Patent Publication No. 2008/0194604 discloses crystalline form B and C of rosuvastatin calcium and hydrates thereof.
U.S. Patent Publication No. 2008/0176878 discloses crystalline form of rosuvastatin calcium, which is being obtained by slurrying amorphous rosuvastatin calcium in water for more than about 10 hours.
PCX Publication No. 2010/081861 discloses crystalline anhydrous rosuvastatin calcium and crystalline rosuvastatin calcium trihydrate forms.
The polymorphic forms of rosuvastatin calcium including amorphous form disclosed in prior-art always contain microbial contamination and therefore there is a need in the art to develop microbial free rosuvastatin calcium and hydrates thereof
SUMMARY OF THE INVENTION:
According to one aspect of the present invention, there is provided a novel crystalline form of rosuvastatin calcium, designated as Form E, characterized by an x-ray powder diffraction pattern having peaks expresses as 2θ at about 3.3, 12.0, 12.7, 13.4, 14.1, 15.1, 16.3, 16.7, 17.1, 17.2, 18.6, 19.5, 20.1, 20.4, 21.3, 22.1, 22.5, 23.2, 25.2, 25.7, 26.2, 26.6, 27.4, 27.8, 29.5, 30.3, 32.5, 33.9, 34.8, 35.9, 37.3 and 39.4 degrees.

According to another aspect of the present invention, there is provided a process for the preparation of crystalline Form E of rosuvastatin calcium comprising slurrying rosuvastatin calcium in water or a mixture of water and isopropanol solvent at a temperature in the range of 90-95°C for a period of 1.5 hours to 3 hours, followed by filtering reaction mixture at a temperature in the range of 25°C to 30°C.
According to another aspect of the present invention, there is provided pharmaceutical composition comprising rosuvastatin crystalline Form E, which is useful as an agent for treating hyperlipidemia, hypercholesterolemia and atherosclerosis.
DETAIL DESCRIPTION OF THE INVENTION:
Rosuvastatin calcium crystalline Form E obtained by following the present invention is free from microbial contamination specifically from the colony of Methylobacterium mesophylicum.
The rosuvastatin calcium crystalline Form E obtained by following the present invention may be characterized by powder X-ray diffraction pattern having following peaks:

Pos. [°2Th.] Height [cts] Area [cts*°2Th.] FWHM [°2Th.] d-spacing
[A] Rel. Int. [%]
3.3 1165.32 190.18 0.1224 26.18758 67.00
12.0 464.52 75.81 0.1224 7.32725 26.71
12.7 359.89 58.73 0.1224 6.92456 20.69
13.4 410.85 100.58 0.1836 6,59644 23.62
14.1 88.69 24.12 0.2040 6.25065 5.10
15.1 106.24 17.34 0.1224 5.82447 6.11
16.3 162.01 35.25 0.1632 5.41826 9.31
16.7 390.70 85.02 0.1632 5.27378 22.46
17.1 880.84 119.79 0.1020 5.15765 50.64

17.2 907.59 74.06 0.0612 5.12643 52.18
18.6 548.52 44.76 0.0612 4.76132 31.54
19.5 393.50 149.85 0.2856 4.53170 22.62 '
20.1 384.38 41.82 0.0816. 4.40236 22.10
20.4 319.73 34.79 0.0816 4.34936 18.38
21.3 204.38 77.83 0.2856 4.15125 11.75
22.1 610.42 132.83 0.1632 4.01291 35.10
22.5 1046.08 85.36 0.0612 3.94123 60.14
23.2 240.54 39.26 0.1224 3.82197 13.83
25.2 108.49 8.85 0.0612 3.52496 6.24
25.7 222.84 18.18 0.0612 3.46057 12.81
26.2 144.30 39.25 0.2040 3.39541 8.30
26.6 189.38 25.76 0.1020. 3.34508 10.89
27.4 60.82 19.85 0.2448 3.24949 3.50
27.8 71.06 15.46 0.1632 3.19950 4.09
29.5 62.42 10.19 0.1224 3.02377 3.59
30.3 137.15 74.61 0.4080 2.94118 7.89
32.5 46.28 4.17 0.0900 2.74543 2.66
33.9 59.95 19.57 0.2448 2.64091 3.45
34.8 71.29 38.78 0.4080 2.56967 4.10
35.9 59.03 19.27 0.2448 2.49580 3.39
37.3 59.84 13.02 0.1632 2.40742 3.44
39.4 88.91 8,00 0.0900 2.28194 5.11
The rosuvastatin calcium crystalline Form E may be characterized by X-ray diffraction pattern as depicted in Figure 1.

The rosuvastatin calcium used for preparing rosuvastatin calcium crystalline Form E may be crystalline (other than Form E) or amorphous in nature.
The water used for preparing rosuvastatin calcium crystalline Form E may be in amount of 8 volumes / weight to 12 volumes / weight of rosuvastatin calcium.
The isopropanol solvent used for preparing rosuvastatin calcium crystalline Form E may be in amount of 0.05 volumes/weight to 1.5 volumes/weight of rosuvastatin calcium.
The slurry of rosuvastatin calcium in water or a mixture of water and isopropanol solvent may be stirred at a temperature in the range of 90-95°C for a period of 1.5 hours to 5 hours and then resulting reaction mixture may be cooled to a temperature in the range of 25°C to 30°C in 1 hour to 4 hours to get rosuvastatin calcium crystalline Form E.
The rosuvastatin calcium crystalline Form E may be isolated by the steps of filtration, centrifugation, washing, drying and combination thereof.
The rosuvastatin calcium crystalline Form E may be washed by a mixture of isopropanol and water at a temperature in the range of 25°C to 30°C.
The mixture of isopropanol and water may contain 5% to 25% of isopropanol.
The rosuvastatin calcium crystalline Form E may be dried at a temperature in the range of 80°C to 120°C for a period of 6 hours to 18 hours.
BRIEF DESCRIPTION OF THE DRAWING:
Figure 1 is a X-ray powder diffraction pattern of crystalline Form E of rosuvastatin calcium.
XRD diffraction measurement was performed on X-Ray powder diffractometer Bruker D8
Advance powder diffractometer with the detector Lynxeye (Bruker). The analysis conditions
were as follows:
Scan range [°2-theta]: 2-39.98;
Scan mode: continuous;

Step size [°2-theta]: 0.0170°; Scan step time[s]: 51.04 seconds; Sample spin: 15 rpm; Sample holder: glass; Measurement Temperature [°C]: 25 Anode Material: Cu K-Alpha[A]: 1.54060
Prior to analysis, the samples were gently ground by means.of mortar and pestle in order to obtain a fine powder. The sample might be mixed with n-dodecane in order to avoid the environment contamination by airborne particles coming from the powder. The ground sample or its suspension with n-dodecane was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.
In the following examples, the preferred aspects of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
EXAMPLE 1: PREPARATION OF FORM E OF ROSUVASTATIN CALCIUM
Amorphous rosuvastatin calcium (20gm) was suspended in water (200ml). The suspension
was heated to 90°C and then it was stirred for 3 hours at 90°C to 95°C. The resulting
suspension was cooled to 25°C and then it was again stirred for 1 hour at 25°C to 30°C and
resulting solids were filtered, washed with a mixture of water and isopropanol 10 ml [water
(9ml) + isopropanol (1ml)] and dried under reduced pressure at 90-95°C for 15 hours.
Yield: 16.4gm
Purity: 99.78% (By HPLC)
XRD pattern (as provided in Figure 1)
EXAMPLE 2: PREPARATION OF FORM E OF ROSUVASTATIN CALCIUM
Amorphous rosuvastatin calcium (200gm) was suspended in a mixture of water (2000ml) and isopropanol (20ml). The suspension was heated to 90°C and then it was stirred for 2.5 hours at 90°C to 95°C. The resulting suspension was cooled to 25°C and then it was again stirred

for I hour at 25°C to 30°C and resulting solids were filtered washed with a mixture of water
and isopropanoi 200 ml [water (180ml) + isopropanol (20ml)] and dried under reduced
pressure at 90-95°C for 15 hours.
Yield: 114gm
Purity: 99.96% (By HPLC)

WE CLAIM:
1. A compound which is rosuvastatin calcium crystalline Form E having substantially the same X-ray diffraction pattern as depicted in Figure 1-
2. The Rosuvastatin crystalline Form E characterized by X-ray powder diffraction pattern having peaks selected from the group comprising of 3.3, 12.0, 12.7, 13.4, 14.1, 15.1, 16.3, 16.7, 17.1, 17.2, 18.6, 19.5, 20.1, 20.4, 21.3, 22.1, 22.5, 23.2, 25.2, 25.7, 26.2, 26.6, 27.4, 27.8, 29.5, 30.3, 32. 5, 33.9, 34.8, 35.9, 37.3 and 39.4 degrees 29.
3. A process for the preparation of crystalline Form E of rosuvastatin calcium comprising slurrying rosuvastatin calcium in wafer or a mixture of water and isopropanol solvent at a temperature in the range of 20-95°C for a period of 1.5 hours to 3 hours, followed by filtering reaction mixture at a temperature in the range of 25°C to 30°C.
4. The process according to claim no. 3 wherein, the rosuvastatin calcium used for preparing rosuvastatin calcium crystalline Form E is crystalline (other than Form E) or amorphous in nature.
5. The process according to claim no. 3 wherein, water used for preparing rosuvastatin calcium crystalline Form E is in amount of 8 volumes / weight to 12 volumes / weight of rosuvastatin calcium.
6. The process according to claim no. 3 wherein, isopropanol solvent used for preparing rosuvastatin calcium crystalline Form E is in amount of 0.05 volumes / weight to 1.5 volumes / weight of rosuvastatin calcium.
7. The process according to claim no. 3 wherein, slurry of rosuvastatin calcium in water or a mixture of water and isopropanol solvent is stired at a temperature in the range of 90-95°C for a period of 1.5 hours to 5 hours and then resulting reaction mixture is

cooled to a temperature in the range of 25°C to 30°C in ] hour to 4 hours to get rosuvastatin calcium crystalline Form E.
8. The process according to claim no. 3 wherein, the rosuvastatin calcium crystalline Form E is washed with a mixture of isopropanol and water at a temperature in the range of 25°C to 30°C.
9. The process according to claim no. 3 wherein, the rosuvastatin calcium crystalline Form E is dried at a temperature in the range of 80°C to 120°C for a period of 6 hours to 18 hours.
10. A pharmaceutical composition comprising rosuvastatin crystalline Form E, which is useful as an agent for treating hyperlipidemia, hypercholesterolemia and atherosclerosis.