FIELD OF THE INVENTION:

The present invention relates to stable crystalline Form of Pitavastatin calcium, i.e. monocalcium bis{(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate}, denominated as Form-M and process for the preparation of the same.

BACKGROUND OF THE INVENTION:

Pitavastatin calcium, i.e., 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.

Pitavastatin was 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 claims 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.

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-M of Pitavastatin calcium, i.e., monocalcium bis {(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3, 5-dihydroxy-6-heptenoate}.

Another object of the present invention is to provide a process for producing the novel crystalline Form-M of Pitavastatin calcium.

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 Pitavastatin calcium Form-M.

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

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

DETAILED DESCRIPTION OF THE INVENTION:

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

The present invention further relates to process for the preparation of stable crystalline Form-M of Pitavastatin calcium.

Instrumentation

Powder X-ray Diffraction (PXRD)
The said cocrystal 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 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 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-M of Pitavastatin calcium.

In one embodiment, crystalline Form-M of Pitavastatin calcium is characterized by the Powder X-ray diffraction having characteristic peaks is given in the following table 1.
Table 1: d-spacings, 20 angles and relative Intensity values of Form-A

In one more embodiment, crystalline Form-M of Pravastatin calcium is further characterized by X-ray powder diffraction as measured by using CuKa radiation, a peak having a relative intensity of less than 25% at a diffraction angle (26) of 30. 16°.

In one more embodiment, crystalline Form-M of Pitavastatin calcium is having a moisture content of 5 to 15%. The moisture content of crystalline Form-M of Pitavastatin calcium is calculated for different batches having a peak having a relative intensity of less than 25% at a diffraction angle (20) of 30. 16° and tabulated in below table 2.

Table 2: moisture content values of crystalline Form-M of Pitavastatin calcium

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

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

The crystalline Form-M of Pitavastatin calcium is further characterized by melting point of 203 ± 5 °C.

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

The physical stability of the polymorphic Form-M of Pitavastatin calcium was determined by storing approximately at 40±2 °C and at 75% relative humidity (RH). The water content of Pitavastatin calcium Form-M also remains unaltered as 8.9. The samples were tested by PXRD, DSC, and TGA after 15 days, 1 month and the observed results are tabulated in Table 3.

Table 3: Stability data of Pitavastatin calcium Form-M brom the above stability data, Pitavastatin calcium Form-M is highly stable at 40±2 °C, 75% relative humidity (RH).

One embodiment of the present invention provides, crystalline Pitavastatin calcium Form-M having HPLC purity of more than 99.8%.

In one more aspect, the present invention provides process for the preparation of crystalline Form-M of Pitavastatin calcium comprising the steps of:

a) dissolving amine salt of Pitavastatin in a mixture of organic solvent and water;
b) adjusting the pH 1-5 by adding an acid
c) optionally removing the organic solvent;
d) dissolving the residue in a mixture of ethereal solvent and water
e) adjusting the pH to 9-13 by adding sodium hydroxide
f) optionally treating with carbon
g) adding calcium acetate
h) isolating and drying the product.

In one embodiment, the amine salt of Pitavastatin calcium is prepared by the conventional prior art methods as known in the literature.

In another embodiment, the organic solvent used in step (a) is selected from ester solvent preferably ethyl acetate.

In one more embodiment, the acid used in the step (b) is hydrochloric acid.

In one more embodiment, the ethereal solvent used in step (d) is selected from t-butyl methyl ether.

In one embodiment, stable Form-M of Pitavastatin calcium is packed in a way to reduce the uptake of moisture and formation of oxidized products, thereby increasing the shelf life of the product. According to the present invention the method for packaging Pitavastatin calcium Form-M comprises of placing the Pitavastatin calcium Form-M in low density polyethylene ("LDPE") bag or High Pressure Low Density Polyethylene ("HP-LDPE") bag under nitrogen atmosphere, placing this bag in triple laminated aluminum linear bag with one oxygen buster, silica gel, optionally molecular sieves and vacuumised nitrogen sealing, placing these both bags into the outer bag of triple laminated aluminum linear bag and vacuumised nitrogen sealing. These poly bags are further placed in closed High Density Polyethylene ("HDPE") drums.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way

Experimental procedure:
Process for the Preparation of crystalline Pitavastatin calcium Form-M
lOOg of (S)-a-methyl benzyl amine salt of Pitavastatin was suspended in a mixture of 500ml of water and 1500ml of ethyl acetate. The pH of the reaction mixture was adjusted to 1.5-4.5 by adding aq. hydrochloric acid. The organic layer was concentrated under vacuum and a mixture of 2000ml of t-butyl methyl ether and 1200ml of water was added. The pH of the reaction mixture was adjusted to 10-13 by using sodium hydroxide solution. The reaction mixture was stirred and layers were separated. 2-3 volumes of water distilled from the reaction mixture and carbon was added to it. The carbon was filtered and washed with 500ml of water. To this calcium acetate solution prepared by dissolving 30g calcium acetate in 500 ml water was added, filtered and dried to yield Pitavastatin Calcium. Yield: 75g Purity: 99.8%.

Pitavastatin calcium Packaging:

3-10 g Pitavastatin calcium Form-M was kept in low density polyethylene ("LDPE") bag or High Pressure Low Density Polyethylene ("HP-LDPE") bag under nitrogen atmosphere. This bag was placed in triple laminated aluminum linear bag with one oxygen buster (1 g sachet) , silica gel (1 g sachet) and molecular sieves (1 g sachet ) under vacuumised nitrogen sealing. This triple laminated aluminum bag was placed in outer triple laminated aluminum linear bag under vacuumised nitrogen sealing. These poly bags are further placed in closed High Density Polyethylene ("HDPE") drums.

We claim:

1. Crystalline Pitavastatin calcium Form-M.

2. The crystalline Pitavastatin calcium Form-M according to claim 1, which contains 5 to 15% water and which shows, in its powder X-ray diffraction chromatogram as measured by using CuKa radiation, a peak having a relative intensity of less than 25% at a diffraction angle (29) of 30. 16° ± 0.2.

3. The crystalline Pitavastatin calcium Form-M according to claim 1, characterized by powder X-ray diffraction as depicted in Figure 1.

4. The crystalline Pitavastatin calcium Form-M according to claim 1, characterized by DSC thermogram as depicted in Figure 2.

5. A method for packaging crystalline Pitavastatin calcium comprising the steps of:

a) placing the Pitavastatin calcium in low density polyethylene ("LDPE") bag or High Pressure Low Density Polyethylene ("HP-LDPE") bag under nitrogen atmosphere;
b) placing this bag in triple laminated aluminum linear bag with one oxygen buster, silica gel, optionally molecular sieves and vacuumised nitrogen sealing;
c) placing these both bags into the outer bag of triple laminated aluminum linear bag and vacuumised nitrogen sealing.

6. The packaging procedure according to claim 5, wherein triple laminated aluminum bags are further placed in closed High Density Polyethylene ("HDPE") drums.