This application claims priority to Indian patent application numbered 3668/CHE/2011 filed on Oct 25, 2011 the contents of which are incorporated by reference in their entirety.

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

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.
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
Pravastatin 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 forms of Pitavastatin calcium.

OBJECT AND SUMMARY OF THE INVENTION

Principle object of the present invention is to provide stable crystalline Forms of Pitavastatin calcium, monocalcium bis{(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate} having moisture content between 5-15%.

The main aspect of the present invention is to provide a stable crystalline Form of Pitavastatin calcium having moisture content between 6-12% at less than or equal to 50 % relative humidity.

Another aspect of the present invention is to provide a stable crystalline Form of Pitavastatin calcium having moisture content between 6-12% at above 50 % relative humidity.

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 crystalline Pitavastatin
Calcium at Relative humidity 30% and 40 %.

Figure 2: illustrates the powder X-ray diffraction pattern of crystalline Pitavastatin
Calcium at Relative humidity 60 %, 70 % and 80 %.

Figure 3: illustrates the powder X-ray diffraction pattern of Pitavastatin Calcium at different temperatures.

Figure 4: illustrates the powder X-ray diffraction pattern of Pitavastatin Calcium after exposing to room temperature humidity.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to stable crystalline Forms 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)

1. PXRD Method: Powder X-ray diffraction measurements were made using Bruker axs D8 Discover powder diffractometer equipped with a goniometer of 0/0 configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted with 1.0 divergence and 1.0 antiscattering slits over the 20 range of 2.0°-50.0° with 0.03° step size and 0.4 seconds step time. The sample preparation performed in controlled humidity condition using dehumidifier. The samples are packed in sample holders and cover the sample using Kapton film and place the sample in a desiccator.

2. The humidity and temperature was controlled by ANSYCO Sycos H-Hot. The samples were measured at different temperatures up to 170°C with a heating rate of 0.2°C/s. The obtained indicates that the most of water is losing below 50°C and at 120 °C the material is becoming amorphous nature. The obtained data showed in Fig.3.

3. The samples packed in dehumidifier conditions with relative humidity ranging from 40±5%RH and PXRD data has been collected. The same sample holder is exposed to air for 15minutes at room temperature humidity the data showed in Fig 4. The data indicates the extra peak enhancement at 6.5, 9.5-10.5( 9.9; 10.4); 13-15 (13.2, 13.7, 14, 14.6) 19-21( 20.5, 20.7, 21); 22-23( 22.9); 24-25.5( 24.1, 25.1) ± 0.2°20.The same sample holder kept under dehumidifier condition for 15 minutes and PXRD data has been collected. The PXRD data resumes original pattern. This experiment confirms that the Pitavastatin calcium PXRD pattern is very sensitive to humidity conditions and small change in humidity conditions leads to the different PXRD patterns.

The main aspect of the present invention is to provide Stable crystalline Form of Pitavastatin calcium having moisture content between 6-12% at less than or equal to 50 % relative humidity.

In one embodiment of the present invention, stable crystalline Form of Pitavastatin calcium having moisture content between 6-12% at less than or equal to 50 % relative humidity is characterized by PXRD pattern as depicted in Figure 1.

In one embodiment of the present invention, crystalline Form of Pitavastatin calcium is stable having moisture content between 6-12% at less than or equal to 50 % relative humidity, preferably 30% & 40 % relative humidity.

In one more embodiment of the present invention, crystalline Form of Pitavastatin calcium having moisture contents between 6-12% is stable at less than or equal to 50 % relative humidity, at ambient temperature.

Another aspect of the present invention is to provide Stable crystalline Form of Pitavastatin calcium having moisture content between 6-12% at above 50 % relative humidity.

In one embodiment of the present invention, stable crystalline Form of Pitavastatin calcium having moisture content between 6-12% at above 50 % relative humidity is characterized by PXRD pattern as depicted in Figure 2.

In one embodiment of the present invention, crystalline Form of Pitavastatin calcium is stable having moisture content between 6-12% at above 50 % relative humidity, preferably 60%, 70 % & 80 % relative humidity.

In one more embodiment of the present invention, crystalline Form of Pitavastatin calcium is stable at above 50 % relative humidity, at ambient temperature.

In another embodiment of the present invention, both the crystalline forms containing moisture content 6 to 12 % of the present invention are packed at 40± 10 % RH in a way to attain the polymorphic stability, there by increasing the shelf life of the product. According to the present invention the method for packaging crystalline Pitavastatin calcium comprises of placing the material in low density polyethylene (LDPE) sealed bag under nitrogen atmosphere, placing the sealed bag in triple laminated aluminum liner bag (inside black color) with one oxygen buster optionally in presence of molecular sieves, optionally silica gel and vacuumised nitrogen sealing, placing this sealed container into outer bag of triple laminated aluminum bag (inside black color) and vacuumised nitrogen sealing and enclosing the triple laminated bag in a closed high density polyethylene (HDPE) drums.

Experimental procedure:

Process for the Preparation of crystalline Pitavastatin calcium.

A mixture of (S)-a-methyl benzyl amine salt of Pitavastatin (100 gm) and DM water (500 ml) were taken in a flask at 30°C .To this slowly sodium hydroxide solution (8.1g sodium hydroxide in 200 ml DM water) was added and stirred at temperature 30°C for 2 hrs. To the reaction mass methyl tert-butyl ether (100 ml) was added. The layers were separated and aqueous layer was washed with methyl tert-butyl ether. DM water was added to the aqueous layer. ~ 100 ml of water was distilled out from the aqueous layer under vacuum below 45°C and cooled the reaction mass at 30°C for 30 min and filtered the reaction mass. To this filtrate filtered calcium chloride (16.25 g calcium chloride dihydrate in 500 ml DM water) solution was added under nitrogen atmosphere and stirred for 2 hrs at temperature 30°C. Solid was filtered under nitrogen. Wet solid was dried with gradually with increase in temperature (25-50 °C) and vacuum (below 100 mbar) till moisture content between 6-12% was attained. Shifting, milling & other operations were carried out during drying to material uniform in nature. 80g material was unloaded under controlled humidity 40± 10 % RH and packed.

Packaging:

The material was packed in LDPE bag under nitrogen atmosphere, twisted and tied with plastic fastener. It was inserted in Triple laminated aluminum liner bag (inside black color) with one oxygen buster and vacuumised nitrogen sealing. Both these bags were then put into the outer bag of triple laminated aluminum bag (inside black color) and vacuumised nitrogen sealing. Such poly bags were further packed in HDPE drums, closed with plastic lids having rubber gasket followed by locking ring and a metal seal and labeled.

We claim:

1. Stable crystalline Form of Pitavastatin calcium having moisture content between 6-12% at less than or equal to 50 % relative humidity.

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

3. The crystalline Form according to claim 1, wherein stable Pitavastatin calcium is stable having moisture content between 6-12% at less than or equal to 50 % relative humidity, preferably 30% & 40 % relative humidity.

4. Stable crystalline Form of Pitavastatin calcium having moisture content between 6-12% at above 50 % relative humidity.

5. The crystalline Form according to claim 5, wherein stable Pitavastatin calcium crystalline form is characterized by the Powder X-ray diffraction as depicted in Figure 2.

6. The crystalline Form according to claim 5, wherein stable Pitavastatin calcium crystalline form is stable having moisture content between 6-12% at above 50 % relative humidity, preferably 60%, 70 % & 80 % relative humidity.

7. A method for packaging crystalline Pitavastatin calcium comprising:

a) placing the crystalline Pitavastatin calcium in low density polyethylene (LDPE) sealed bag under nitrogen atmosphere,

b) placing the sealed bag in triple laminated aluminum liner bag with one oxygen buster optionally in presence of molecular sieves, silica gel and vacuumised nitrogen sealing, and

c) placing the above sealed container in triple laminated aluminum bag, vacuumised nitrogen sealing and enclosing the triple laminated bag in a closed high density polyethylene (HDPE) drums.