POLYMORPHIC FORMS OF PITAVASTATIN SODIUM

Abstract

The present invention is directed to polymorphic forms of Pitavastatin sodium and processes for preparation of the same.

Claims

1. Crystalline Form-I of Pitavastatin sodium and hydrates thereof, wherein the crystalline Form-I of Pitavastatin sodium has an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 9.36, 10.32, 13.33, 14.14, 18.70, 21.18, 21.51, 22.87, 23.27, and 24.90.

2. Crystalline Form-I of Pitavastatin sodium and hydrates thereof, wherein the crystalline Form-I of Pitavastatin sodium has an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 4.65, 8.44, 9.36, 10.32, 13.33, 14.14, 17.73, 18.70, 19.81, 21.18, 21.51, 22.87, 23.27, and 24.90.

3. The crystalline Form-I of Pitavastatin sodium as claimed in claim 1 having an X-ray powder diffraction pattern substantially same as that shown in FIG. 1.

4. The crystalline Form-I of Pitavastatin sodium as claimed in claim 1, wherein hydrate is in the form of monohydrate.

5. A process for the preparation of crystalline Form-I of Pitavastatin sodium, which comprises the steps of: (a) reacting pitavastatin acid with aqueous sodium hydroxide solution; (b) adding acetonitrile to the solution obtained in step (a); and (c) isolating the crystalline Form-I.

6. Crystalline Form-II of Pitavastatin sodium and hydrate thereof, wherein the crystalline Form-II of Pitavastatin sodium has an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 8.35, 10.00, 13.38, 16.76, 19.02, 20.06, 22.95 and 25.25.

7. Crystalline Form-II of Pitavastatin sodium and hydrates thereof, wherein the crystalline Form-II of Pitavastatin sodium has an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 4.17, 5.78, 8.35, 10.00, 11.64, 13.38, 14.31, 14.93, 16.76, 17.68, 19.02, 20.06, 20.45, 21.31, 22.30, 22.95, 23.55, 24.76, 25.25, 25.89, 28.32, 29.48 and 30.08.

8. The crystalline Form-II of Pitavastatin sodium as claimed in claim 6 having an X-ray powder diffraction pattern substantially same as that shown in FIG. 2.

9. The crystalline Form-II of Pitavastatin sodium as claimed in claim 6, wherein the hydrate is in the form of pentahydrate.

10. A process for the preparation of crystalline Form-II of Pitavastatin sodium, which comprises the steps of: (a) reacting pitavastatin acid with aqueous sodium hydroxide solution; (b) adding acetonitrile to the solution obtained in step (a); (c) isolating the solid; and (d) exposing the solid isolated in above step (c) an atmosphere with relative air humidity at about 60% to yield crystalline Form-II.

11. An amorphous form of pitavastatin sodium.

12. The amorphous form of pitavastatin sodium as claimed in claim 11 having an X-ray powder diffraction pattern substantially same as that shown in FIG. 3.

13. A process for the preparation of an amorphous form of Pitavastatin sodium, which comprises the steps of: (a) adding pitavastatin sodium into an alcohol; (b) distilling the alcohol of step (a); and (c) isolating the amorphous form of Pitavastatin sodium.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0017] FIG. 1: PXRD pattern of the crystalline form-I of Pitavastatin Sodium.

[0018] FIG. 2: PXRD pattern of the crystalline form-II of Pitavastatin Sodium.

[0019] FIG. 3: PXRD pattern of the amorphous form of Pitavastatin Sodium.

DETAILED DESCRIPTION OF THE INVENTION

[0020] Accordingly, the present invention relates to novel polymorphic forms of Pitavastatin sodium.

[0021] In an embodiment, the present invention provides novel crystalline Form-I of Pitavastatin sodium.

[0022] In accordance with the present invention, the crystalline Form-I of Pitavastatin sodium is a hydrate, preferably monohydrate.

[0023] In an embodiment of the invention provides crystalline Form-I of Pitavastatin sodium characterized by a distinctive PXRD pattern. More specifically such a PXRD pattern is characterized by peaks at 9.36, 10.32, 13.33, 14.14, 18.70, 21.18, 21.51, 22.87, 23.27, and 24.90±0.2 degree 2θ.

[0024] In another embodiment, the crystalline Form-I of Pitavastatin sodium is further characterized by a PXRD pattern having characteristic peaks at 4.65, 8.44, 9.36, 10.32, 13.33, 14.14, 17.73, 18.70, 19.81, 21.18, 21.51, 22.87, 23.27, and 24.90±0.2 degree 2θ.

[0025] The PXRD pattern of the crystalline Form-I is shown in FIG. 1.

[0026] In yet another embodiment of the present invention provides novel crystalline Form-II of Pitavastatin sodium.

[0027] In accordance with the present invention, the crystalline Form-II of Pitavastatin sodium is hydrate, preferably pentahydrate.

[0028] In an embodiment of the invention provides crystalline Form-II of Pitavastatin sodium characterized by a distinctive PXRD pattern. More specifically such a PXRD pattern is characterized by peaks at 8.35, 10.00, 13.38, 16.76, 19.02, 20.06, 22.95 and 25.25±0.2 degree 2θ.

[0029] In another embodiment, the crystalline Form-II of Pitavastatin sodium is further characterized by a PXRD pattern having characteristic peaks at 4.17, 5.78, 8.35, 10.00, 11.64, 13.38, 14.31, 14.93, 16.76, 17.68, 19.02, 20.06, 20.45, 21.31, 22.30, 22.95, 23.55, 24.76, 25.25, 25.89, 28.32, 29.48 and 30.08±0.2 degree 2θ.

[0030] The PXRD pattern of the crystalline Form-II is shown in FIG. 2.

[0031] The crystalline Form-I of Pitavastatin sodium of the present invention is prepared from Pitavastatin acid of the formula (1). The Pitavastatin acid is taken in water and cooled to 0-20° C. temperature, preferably to 5-20° C. temperature, more preferably to 15-20° C. temperature.

[0032] Thereafter aqueous sodium hydroxide is gradually added to the reaction mixture at the same temperature. The reaction mixture is stirred for 15-180 min, preferably for 60-120 min, more preferably for 30-45 min, at 0-20° C. temperature, preferably at 5-20° C. temperature, more preferably at 15-20° C. temperature. Thereafter ethyl acetate is added to the reaction mixture. The reaction mixture is stirred for 15-20 min and the layers are separated. The aqueous layer is filtered and acetonitrile is added gradually to the reaction mixture at 0-20° C. temperature, preferably at 5-20° C. temperature, more preferably at 15-20° C. temperature till the precipitation is completed.

[0033] The reaction mixture is further cooled to 0-20° C. temperature, preferably to 5-20° C. temperature, more preferably to 5-8° C. temperature and stirred for 1-8 hours, preferably for 1-5 hours, more preferably for 2-3 hours. The precipitated solid is collected by filtration and is dried at 40-80° C. temperature, preferably at 40-60° C. temperature, more preferably at 45-50° C. temperature under vacuum for 5-24 hours, preferably for 5-18 hours, more preferably for 10-12 hours to afford Pitavastatin Sodium crystalline Form-I.

[0034] The crystalline Form-II of Pitavastatin sodium of the present invention is prepared from Pitavastatin acid of the formula (1). The Pitavastatin acid is taken in water and cooled to 0-20° C. temperature, preferably to 5-20° C. temperature, more preferably to 15-20° C. temperature. Thereafter aqueous sodium hydroxide is gradually added to the reaction mixture at the same temperature. The reaction mixture is stirred for 15-180 min, preferably for 60-120 min, more preferably for 30-45 min, at 0-20° C. temperature, preferably at 5-20° C. temperature, more preferably at 15-20° C. temperature. Thereafter ethyl acetate is added to the reaction mixture. The reaction mixture is stirred for 15-20 min and the layers are separated. The aqueous layer is filtered and acetonitrile is added gradually to the reaction mixture at 0-20° C. temperature, preferably at 5-20° C. temperature, more preferably at 15-20° C. temperature till the precipitation is completed.

[0035] The reaction mixture is further cooled to 0-20° C. temperature, preferably to 5-20° C. temperature, more preferably to 5-8° C. temperature and stirred for 1-8 hours, preferably for 1-5 hours, more preferably for 2-3 hours. The precipitated solid is collected by filtration and dried at 40-80° C. temperature, preferably at 40-60° C. temperature, more preferably at 45-50° C. temperature under vacuum for 5-24 hours, preferably for 5-18 hours, more preferably for 10-12 hours. The dried solid is kept at 25-30° C. temperature and 60±5 RH (relative humidity) for 18-24 hours to afford Pitavastatin Sodium crystalline Form-II.

[0036] Alternatively, the crystalline Form-II is also prepared by drying the wet solid obtained after filtration.

[0037] In yet another embodiment, the Pitavastatin Sodium Form-I is converted to Pitavastatin Sodium Form-II.

[0038] In an embodiment, the present invention provides an amorphous form of Pitavastatin sodium.

[0039] In yet another embodiment, the present invention provides an amorphous form of Pitavastatin sodium characterized by PXRD.

[0040] The PXRD pattern of an amorphous form of Pitavastatin sodium is shown in FIG. 3.

[0041] The amorphous form of Pitavastatin sodium is prepared from Pitavastatin sodium Form-I and/or Form-II of the present invention. The Pitavastatin Form-I and/or Form-II is taken in an alcoholic solvent and the solvent is removed. Suitable techniques for solvent removal include using a rotational distillation device such as a rotary evaporator instrument, spray drying, agitated thin film drying, freeze drying (lyophilization), and the like.

[0042] The alcoholic solvent used for the preparation of the amorphous form is selected from the group of C1 to C5 straight or branched chain alcohol. Suitable solvents include, although not limited to, ethanol, methanol, isopropanol and the like.

[0043] The Pitavastatin acid, as used in the present invention, can be prepared lay a process generally known in the art or by a novel process.

[0044] The Form-I, Form-II and amorphous form of Pitavastatin sodium of the present invention is used as HMG-CoA reductase inhibitors.

[0045] Another aspect of the present invention is to provide pharmaceutical compositions comprising an effective amount of crystalline Form-I or Form-II or an amorphous form of Pitavastatin sodium and a pharmaceutical acceptable carrier.

[0046] These polymorphic forms may be used as single component or as mixtures with other crystalline form or an amorphous form.

[0047] The polymorphic forms of Pitavastatin sodium of the present invention may be used to prepare pharmaceutical composition for the reduction of elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG) and to increase high-density lipoprotein cholesterol (HDL-C). Such pharmaceutical composition can be prepared by the methods known in the literature.

[0048] The present invention is further illustrated with the following non-limiting examples.

EXAMPLE-1

Preparation of Pitavastatin Sodium (Form-I)

[0049] A mixture of 40.0 gm Pitavastatin acid and 120 ml water was cooled to 15-20° C. temperature. Thereafter aqueous solution of sodium hydroxide (4.0 gm) in water (20 ml) was added to the reaction mixture. The reaction mixture was stirred for 30-45 min at 15-20° C. temperature. Ethyl acetate (80 ml) was added into the reaction mixture at 15-20° C. temperature, stirred for 15-20 min and the layers were separated. The aqueous layer was filtered and acetonitrile (1200 ml) was gradually added to the aqueous layer under stirring till the precipitation was completed. The reaction mixture was cooled to 5-8° C. temperature and stirred for 2-3 hours at 5-8° C. temperature. The precipitated solid was filtered, washed with acetonitrile (40m1) and dried at 45-50° C. temperature under vacuum for 10-12 hours to afford the title compound (28.0 gm).

[0050] Yield (w/w): 0.70 (66.0%)

[0051] HPLC purity: 99.70%

EXAMPLE-2

Preparation of Pitavastatin Sodium (Form-II)

[0052] A mixture of 40.0 gm of Pitavastatin acid and 120 ml of water was cooled to 15-20° C. temperature under stirring. Thereafter aqueous solution of sodium hydroxide (4.0 gm) in water (20 ml) was added to the reaction mixture. The reaction mixture was stirred for 30-45 min at 15-20° C. temperature. Ethyl acetate (80 ml) was added to the reaction mixture at 15-20° C. temperature, stirred for 15-20 min and the layers were separated. The aqueous layer was filtered and acetonitrile (1200 ml) was gradually added to the aqueous layer under stirring till the precipitation was completed. The reaction mixture was cooled to 5-8° C. temperature and stirred for 2-3 hours at 5-8° C. temperature. The precipitated solid was filtered, washed with acetonitrile (40 ml) and dried at 45-50° C. temperature under vacuum for 10-12 hours and kept in a petri dish at 25-30° C. and 60±5 RH (relative humidity) for 18-24 hours to afford the title compound (31.6 gm).

[0053] Yield (w/w): 0.79 (65.8%)

[0054] HPLC purity: 99.70%

EXAMPLE-3

Preparation of Pitavastatin Sodium Amorphous

[0055] Pitavastatin sodium (3.0 gm) and ethanol (60 ml) were taken in a round bottomed flask at 25-30° C. temperature. The reaction mixture was filtered and the solvent was distilled off on rotatory evaporator under vacuum maintaining bath temperature at 45-50° C. temperature. Thereafter the reaction mixture was degassed under vacuum for 2-3 hours to afford the title compound (2.8 gm).

[0056] HPLC purity: 99.70%.