This application claims priority to Indian patent application no 3124/CHE/2009 filed on Dec 17, 2009 the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to novel polymorphic Forms of Bis [(E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S)-3, 5-dihydroxyhept-6-enoic acid] Calcium Salt (Rosuvastatin Calcium) and process for preparation of the same.

BACKGROUND OF THE INVENTION

Bis[(E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]Calcium Salt of Formula (I) (Rosuvastatin Calcium) is an HMG-CoA reductase inhibitor, developed by shionogi for the treatment of hyperlipidaemia.

Rosuvastatin calcium is marketed under the proprietary name CRESTOR for treatment of mammals such as human and administrated as daily dosage form of 5 mg, 10 mg, 20 mg and 40 mg.

European patent publication EP 0521471, discloses Rosuvastatin and its pharmaceutically acceptable salts including calcium salt of Rosuvastatin. This patent discloses Rosuvastatin calcium, which is prepared by dissolving the corresponding sodium salt in water, adding calcium hloride and collecting the resultant precipitate by filtration. US Pat No. US 6,589,959 further confirms that Rosuvastatin Calcium obtained according to this process is amorphous Form.

US Pat No. US 6,589,959 discloses a crystalline Form of Rosuvastatin calcium, designated as Form-A having an X-ray powder diffraction pattern with specific peaks at 2-theta = 4.92, 11.50, 6.93, 9.35, 23.12 and 18.76°.

WO 2005/023779 discloses two crystalline Forms B and B-l of Rosuvastatin calcium whereas Form B of Rosuvastatin calcium having an X-ray powder diffraction pattern with specific peaks at 2-theta = 8.8, 13.1 and 21.5° and Form B-l of Rosuvastatin calcium having an X-ray powder diffraction pattern with peaks at 2-theta = 4.4, 7.7, 9.0 and 20.7°.

US 2008/0176878 discloses a crystalline Form of Rosuvastatin calcium having an X-ray powder diffraction pattern with specific peaks at 2-theta = 4.7,19.4 and 22.3°.
The present invention provides stable and industrially scalable polymorphic Forms of
Rosuvastatin calcium.

OBJECT & SUMMARY OF THE INVENTION

It is a principal object of the present invention to provide novel polymorphic forms of bis [(E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S)-3, 5-dihydroxyhept-6-enoic acid] calcium Salt characterized by X-Ray powder diffraction pattern (PXRD), differential scanning calorimetric (DSC) thermogram and thermogravimetric analysis (TGA).

Another main object of the present invention is to provide a process for producing the novel polymorphic Forms of Rosuvastatin calcium.

The present invention is further attained and supported by the following embodiments described herein. however, the scope of the invention is not restricted to the described embodiments herein after

In accordance with one more embodiment of the present invention, there is provided novel
polymorphic Form S of Rosuvastatin calcium characterized by PXRD and DSC

In accordance with one embodiment of the present invention, there is provided crystalline Form R of Rosuvastatin calcium characterized by PXRD, DSC and TGA

In accordance with another preferred embodiment of the present invention, there is provided a process for producing crystalline Form R of Rosuvastatin calcium comprising, adding Rosuvastatin calcium to a mixture of organic solvent and water, heating the resultant mixture, cooling and isolating the crystalline Form R.

In accordance with one more preferred embodiment of the present invention, there is provided a process for producing novel polymorphic Form S of Rosuvastatin calcium comprising, adding (S)-(-)-a-methyl benzyl amine salt of Rosuvastatin to a mixture of ester solvent and water, adjusting the pH to acidic, concentrating the organic layer, adding obtained residue to a mixture of organic solvent and water, adjusting the pH to basic and separating the layers, reducing the aqueous layer by distillation, seeding with amorphous Rosuvastatin calcium followed by the addition of calcium source and isolating the polymorphic Form S of Rosuvastatin calcium.

DESCRIPTION OF THE DRAWINGS:

Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures wherein :

Figure 1: illustrates the characteristic X-ray powder diffraction (PXRD) of crystalline Rosuvastatin calcium Form R.

Figure 2: illustrates the characteristic differential scanning calorimetric (DSC) thermogram of
crystalline Rosuvastatin calcium Form R.

Figure 3: illustrates the characteristic thermogravimetric analysis (TGA) spectrum of crystalline Rosuvastatin calcium Form R.

Figure 4: illustrates the characteristic X-ray powder diffraction (PXRD) of polymorphic
Rosuvastatin calcium Form S.

Figure 5: illustrates the characteristic differential scanning calorimetric (DSC) thermogram of
polymorphic Rosuvastatin calcium Form S.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to novel polymorphic forms of bis [(E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S)-3, 5-dihydroxyhept-6-enoic acid] Calcium salt herein designated as Form R and Form S

The present invention also relates to novel process for the preparation of polymorphic Forms R and S of Rosuvastatin calcium.

Powder X-ray Diffraction (PXRD)
The polymorphs of the present invention are characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of the polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of 0/0 configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2-theta range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.

Differential scanning calorimetric (DSC)
The DSC measurements were carried out on Mettler Toledo 822 stare and TA Q1000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a
temperature range of 30°C-300°C purging with nitrogen at a flow rate of 50ml/min. Standard aluminum crucibles covered by lids with three pin holes were used.

Thermogravimetric analysis (TGA)

TGA was recorded on out using the instrument Mettler Toledo TGA/SDTA 85 le and TGA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 25ml/min.

According to the present invention the novel crystalline Form R of Rosuvastatin calcium is characterized by an X-ray powder diffraction pattern having peaks at about 4.08, 4.55, 5.8, 6.3, 8.93, 9.6 and 18.01° (±) 0.2° 2-theta. The crystalline Form R of Rosuvastatin calcium may also be substantially identified by the PXRD pattern depicted in Figure 1.

The crystalline Form R of Rosuvastatin calcium may be further characterized by a DSC thermogram as depicted in Figure 2.
The crystalline Form R of Rosuvastatin calcium may be further characterized by a TGA spectrum as depicted in Figure 3, which is showing ~ 5.6 % loss of moisture content.

According to the present invention there is provided a process for the preparation of crystalline Form R of Rosuvastatin calcium adding Rosuvastatin calcium to a mixture of organic solvent and water, heating the resultant mixture, cooling and isolating the crystalline Form R.

In one embodiment of the present invention, the organic solvent is preferably methyl t-butyl ether (MTBE).

As per the present invention, Rosuvastatin calcium is added to a mixture of organic solvent and water preferably the organic solvent is methyl t-butyl ether (MTBE). The resultant mixture is heated, and cooled to 0-10 °C. And novel crystalline Form R of Rosuvastatin calcium is isolated.

According to the present invention the polymorphic Form S of Rosuvastatin calcium is characterized by an X-ray powder diffraction pattern having peaks at about 3.5, 4.2 and 6.8° (±) 0.2° 2-theta. The polymorphic Form S of Rosuvastatin calcium may also be substantially identified by the PXRD pattern depicted in Figure 4.

The polymorphic Form S of Rosuvastatin calcium may be further characterized by a DSC thermogram as depicted in Figure 5.

According to the present invention there is provided a process for producing novel polymorphic Form S of Rosuvastatin calcium comprising, adding (S)-(-)-a-methyl benzyl amine salt of Rosuvastatin to a mixture of ester solvent and water, adjusting the pH to acidic, concentrating the organic layer, adding obtained residue to a mixture of organic solvent and water, adjusting the pH to basic and separating the layers, reducing the aqueous layer by distillation, seeding with amorphous Rosuvastatin calcium followed by the addition of calcium source and isolating the polymorphic Form S of Rosuvastatin calcium.

In one embodiment of the present invention, the ester solvent is preferably ethyl acetate.

In one embodiment of the present invention, pH is adjusted to acidic by using mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, preferably hydrochloric acid.

In one embodiment of the present invention, the organic solvent is preferably methyl t-butyl ether (MTBE).

In one embodiment of the present invention, pH is adjusted to basic by using a base selected
from alkali metal hydroxides such as sodium hydroxide.

In one embodiment of the present invention, calcium source is calcium acetate.

In another embodiment of the present invention, process for the preparation of crystalline Rosuvastatin calcium Form S comprising the steps of: providing Rosuvastatin sodium salt in
aqueous medium, seeding with Rosuvastatin calcium, adding a source of calcium, and isolating the polymorphic Form S of Rosuvastatin calcium.

As per the present invention, (S)-(-)-a-methyl benzyl amine salt of Rosuvastatin is added to a mixture of ester solvent preferably ethyl acetate, and water. The pH of the reaction mixture is adjusted 3-4 by the addition of acid preferably hydrochloric acid. Ethyl acetate layer is separated and concentrated. The obtained residue is added to a mixture of organic solvent and water preferably the organic solvent is methyl t-butyl ether (MTBE). The pH of the reaction mixture is adjusted to 10-12 by using a base preferably sodium hydroxide and aqueous layer is washed with methyl t-butyl ether. The obtained aqueous layer is distilled, preferably to l/3rd of aqueous layer is distilled off, and seeded with amorphous Rosuvastatin Calcium followed addition of calcium acetate solution in water. And novel polymorphic Form S of Rosuvastatin calcium is isolated.

According to the present invention, the Rosuvastatin calcium used herein is selected from the group consisting of but not limited to crystalline or amorphous form or any solvate.

The following examples are provided to illustrate the process of present invention. They are however, not intended to limiting the scope of the present invention in any way and several variants of these examples would be evident to person ordinarily skilled in the art.

Example-l: Preparation of Rosuvastatin calcium Form R
Rosuvastatin calcium (10 gm) was added to the mixture of methyl t-butyl ether (600 ml) and water (10 ml) and heated to 45-60 °C for 15 minutes. The reaction mass was cooled to room temperature and further cooled to 0-5 °C and stirred for 1-2 days. The reaction mass was filtered and dried under vacuum to yield crystalline Rosuvastatin calcium Form R.

Example-2: Preparation of Rosuvastatin calcium Form S
(S)-(-)-a-methyl benzyl amine salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl) amino] pyrimidin-5-yl]-(3R, 5S)-3, 5-dihydroxyhept-6-enoic acid (5 gm) was added to a mixture of ethyl acetate (50ml) and water (25ml) and cooled to 0-10 °C. The pH of the reaction mixture was adjusted to 2-4 by using dilute hydrochloric acid. The two layers were separated and ethyl acetate layer was concentrated under reduced pressure to get residue. The obtained residue was added to a mixture of Methyl t-butyl ether (50ml) and water (50ml). The pH of the reaction mixture was adjusted to 10-12 using aqueous sodium hydroxide solution. The separated aqueous layer was washed with Methyl t-butyl ether and reduced by distillation and seeded with amorphous Rosuvastatin Calcium (250 mg) followed addition of calcium acetate solution in water. The reaction mixture was filtered and dried to yield polymorphic Form S of Rosuvastatin calcium.

We claim:

1. A process for the preparation of crystalline Rosuvastatin calcium Form R comprising the steps of:

a) adding Rosuvastatin calcium to a mixture of organic solvent and water;
b) heating the resultant mixture;
c) cooling; and
d) isolating crystalline Form R of Rosuvastatin calcium.

2. The process according to claim 1, wherein the organic solvent is methyl t-butyl ether (MTBE).

3. Rosuvastatin calcium Form R as obtained in claims 1-2.

4. A process for the preparation of crystalline Rosuvastatin calcium Form S comprising the steps of:

a) providing Rosuvastatin sodium salt in aqueous medium;
b) seeding with Rosuvastatin calcium;
c) adding a source of calcium; and
d) isolating crystalline Form S of Rosuvastatin calcium.

5. Rosuvastatin calcium Form S as obtained in claim 4