This application claims priority to Indian patent application numbered 1928/CHE/2011 filed on Jun 07,2011 the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION:

The present invention relates to stable crystalline Form of Pitavastatin calcium, monocalcium bis{(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate}, denominated as Form-P.

BACKGROUND OF THE INVENTION:

Pitavastatin calcium, monocalcium bis{(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate}, having the Formula-I is approved, under the trade name Livalo®, by the United States Food and Drug Administration. Livalo® is a HMG-CoA reductase inhibitor indicated for the treatment of patients with primary hyperlipidemia and mixed Dyslipidemia.

Formula-I

Pitavastatin is first disclosed in United States patent number US 5753675 and this patent does not disclose calcium salt of Pitavastatin.

United States patent number US 5856336 specifically discloses calcium salt of Pitavastatin and this patent does not discloses process for the preparation of Pitavastatin calcium.

Synthetic procedure for the preparation of Pitavastatin calcium is described in United States patent number US 5473075. In this process Pitavastatin calcium obtained as a white crystalline material with a melting point of 190-192 °C after decomposition.

US 20090182008 discloses crystalline Forms A, B, C, D, E and F, and the amorphous Form of Pitavastatin calcium. This patent application also discloses process for the preparation of the crystalline Forms A, B, C, D, E and F, and the amorphous Form of Pitavastatin calcium. The melting point of the Form-A is given as 95 °C in this patent publication.

US 20090176987 discloses crystalline Form-A of Pitavastatin calcium contains 5 to 15% of water and which shows, in its X-ray powder diffraction as measured by using CuKa radiation, a peak having a relative intensity of more than 25% at a diffraction angle (20) of 30. 16°.

The present invention provides stable and industrially scalable crystalline form of Pitavastatin calcium.

OBJECT AND SUMMARY OF THE INVENTION:

Principle object of the present invention is to provide novel crystalline Form-P of Pitavastatin calcium, monocalcium bis{(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate}. Another object of the present invention also provides process for the preparation of novel crystalline Form-P.

BRIEF 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 powder X-ray diffraction pattern of Pravastatin calcium Form-P.

Figure 2: illustrates DSC thermogram of Pitavastatin calcium Form-P.

Figure 3: illustrates TGA of Pitavastatin calcium Form-P.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to stable crystalline Form-P of Pitavastatin calcium, monocalcium bis{(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate}.

Instrumentation:

Powder X-ray Diffraction (PXRD)

The said polymorph of the present invention is characterized by their X-ray powder diffraction pattern.

Thus, the X-ray diffraction patterns of said polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of 6/0 configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 20 range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.

Differential Scanning Calorimetry (DSC)

The DSC measurements were carried out on 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.

Thermo gravimetric Analysis (TGA)

TGA/DTA was recorded using the instrument TA 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.

The main aspect of the present invention is to provide Stable crystalline Form-P of Pitavastatin calcium.
In one embodiment, crystalline Form-P of Pitavastatin calcium is characterized by the Powder X-ray diffraction having characteristic peaks 5.40, 5.78, 9.08, 13.67, 21.28 and 21.74 (±) 0.2° 2-theta.

In another embodiment, crystalline Form-P of Pitavastatin calcium is further characterized by the Powder X-ray diffraction having characteristic peaks 4.49, 5.40, 5.78, 8.18, 9.08, 10.26, 10.90, 11.56, 13.31, 13.67, 14.29, 15.19, 16.32, 17.63, 18.48, 19.92, 20.68, 21.28, 21.74, 22.64, 24.08, 24.38, 25.79 and 28.66 (±) 0.2° 2-theta.

In one more embodiment, crystalline Form-P of Pitavastatin calcium is further characterized by the Powder X-ray diffraction as depicted in Figure 1.

The crystalline Form-P of Pitavastatin calcium is further characterized by DSC thermogram as depicted in Figure 2.

The crystalline Form-P of Pitavastatin calcium is further characterized by TGA as depicted in Figure 3.

The physical stability of the polymorphic Form-P of Pitavastatin calcium was determined by exposing the Pitavastatin calcium approximately at 90% relative humidity (RH) for 24 hours and exposed to atmosphere for 24 hours. The samples were tested by PXRD and the form is unaltered. This test shows that the present novel Form-P is stable form.

Another aspect of the present invention is to provide process for the preparation of crystalline Form-P of Pitavastatin calcium comprising the steps of:

a) reacting (S)-(-)-a-methyl benzyl amine salt of Pitavastatin with aqueous sodium hydroxide solution,

b) adding calcium chloride to the reaction mixture, and

c) isolating Pitavastatin calcium Form-P.

In one embodiment, after addition of the calcium chloride the reaction mixture is filtered and washed with water and dried at a temperature of 45 - 55°C preferably 50 °C.

Experimental procedure:

Process for the Preparation of crystalline Pitavastatin calcium Form-P

To (S)-(-)-a-methyl benzyl amine salt of Pitavastatin (15.0 g), water (250 ml) and sodium hydroxide solution (1.2 g sodium hydroxide dissolved in 30 ml DM water) was added and stirred for dissolution at room temperature. To this solution calcium chloride solution (2.43 g Calcium chloride dihydrate dissolved in 250 ml DM water) was added. The reaction mixture was stirred, filtered and washed with water. The obtained compound was dried u/v below 50 °C to give Pitavastatin calcium Form-P.

Results: Dry weight 8.2 g

We claim:

1. A crystalline Pitavastatin calcium Form-P.

2. The crystalline Form-P according to claim 1, wherein Pitavastatin calcium Form-P is characterized by the Powder X-ray diffraction having characteristic peaks 5.40, 5.78, 9.08, 13.67, 21.28 and 21.74 (±) 0.2° 2-theta.

3. The crystalline Form-P according to claim 1, wherein Pitavastatin calcium Form-P is characterized by the Powder X-ray diffraction having characteristic peaks 4.49, 5.40, 5.78, 8.18, 9.08, 10.26, 10.90, 11.56, 13.31, 13.67, 14.29, 15.19, 16.32, 17.63, 18.48, 19.92, 20.68, 21.28, 21.74, 22.64, 24.08, 24.38, 25.79 and 28.66 (±) 0.2° 2-theta.

4. The crystalline Form-P according to claim 1, wherein Pitavastatin calcium Form-P is characterized by the Powder X-ray diffraction as depicted in Figure 1.

5. The crystalline Form-P according to claim 1, wherein Pitavastatin calcium Form-P is characterized by DSC thermogram as depicted in Figure 2.

6. The crystalline Form-P according to claim 1, wherein Pitavastatin calcium Form-P is characterized by TGA as depicted in Figure 3.

7. A process for the preparation of crystalline Form-P of Pitavastatin calcium comprising the steps of:

a) reacting (S)-(-)-a-methyl benzyl amine salt of Pitavastatin with aqueous sodium hydroxide solution,

b) adding calcium chloride to the reaction mixture, and

c) isolating Pitavastatin calcium Form-P.