FIELD OF THE INVENTION

The present invention relates to a polymorphic form of Atorvastatin calcium of Formula I, as depicted in Figure 1.

BACKGROUND OF THE INVENTION

Atorvastatin is a member of the class of drugs called statins. Statin drugs are currently the most therapeutically effective drugs available for reducing low density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease. A high level of LDL in the bloodstream has been linked to the formation of coronary lesions which obstruct the flow of blood and can rupture and promote thrombosis.

Atorvastatin is chemically known as [R-(R*,R*)]-2-(4-fluorophenyl)-p,6-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid.

Atorvastatin is marketed as the hemi calcium salt trihydrate under the trade name LIPITOR® by Pfizer.

Atorvastatin was first disclosed to the public and claimed in US 4,681,893. The Atorvastatin calcium salt is disclosed in US 5,273,995. This patent teaches that the calcium salt is obtained by crystallization from a brine solution resulting from the transposition of the sodium salt with CaCl2 and further purified by recrystallization from a 5:3 mixture of ethyl acetate and hexane.

Polymorphism is the property of some molecules and molecular complexes to assume more than one crystalline or amorphous form in the solid state. A single molecule, like the Atorvastatin or the salt complex, may give rise to a variety of solids having distinct physical properties like solubility, X-ray diffraction pattern and solid state 13C NMR spectrum. The differences in the physical properties of polymorphs result from the orientation and intermolecular interactions of adjacent molecules (complexes) in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula, which may be thought of as analogous to a unit cell in metallurgy, yet having distinct advantageous and/or disadvantageous physical properties compared to other forms in the polymorph family. One of the most important physical properties of pharmaceutical polymorphs is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient.

US 5,969,156 discloses three polymorphs of Atorvastatin designated Form I, II, and IV. US 6,121,461 discloses crystalline Atorvastatin Form III. US 7,144,916 discloses Atorvastatin Form VI. US 7,538,136 B2 discloses Form X, A, B, B2, C D and E. WO 03/070702 Al and WO 2004/043918 A2 discloses different crystalline forms of Atorvastatin. US 2008/0306282 Al discloses different crystalline forms which are designated as Form XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX.

We have now found a polymorphic form of Atorvastatin calcium, as depicted in Figure 1, which is stable, reproducible and suitable for preparing pharmaceutical dosage forms.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a polymorphic form of Atorvastatin calcium, which is stable and reproducible.
In yet another objective of the present invention is to provide a process for the preparation of polymorphic form of Atorvastatin calcium.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 - Powder X-ray diffraction (PXRD) of Atorvastatin calcium Figure 2 - Differential Scanning Calorimetry (DSC) of Atorvastatin calcium

SUMMARY OF THE INVENTION

The present invention relates to a polymorphic form of Atorvastatin calcium of Formula I, as depicted in Figure 1,

which is having at least one of the following properties:

a) a powder X-ray diffraction pattern with reflections at about 2.78, 5.1, 7.8 ±0.2 °29 and broad diffraction intensity is observed in the range between 15°and25°29;

b) a differential scanning calorimetry (DSC) endothermic peak at about 165-180°C.

The present invention also provides a process for its preparation of polymorphic form of Atorvastatin calcium, as depicted in Figure 1, which comprises addition of aqueous calcium acetate solution to atorvastatin sodium and washing the obtained product using ethanol:water mixture, followed by methyl tert-butyl ether and finally with hot water.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to polymorphic form of Atorvastatin calcium of Formula I, as depicted in Figure 1, which is characterized by a powder X-ray diffraction pattern substantially as depicted in Figure-1. Further the new polymorphic form of Atorvastatin calcium has characteristic peaks at 2.78 ± 0.2, 5.1 ± 0.2, 7.8 ± 0.2 and broad diffraction intensity is observed in the range between 15 and 25 °29 values.

In another embodiment, crystalline polymorphic form of Atorvastatin calcium of Formula I, is further characterized by having a Differential Scanning Calorimetry (DSC) endothermic peak at about 165 - 180°C.

In another embodiment the present invention also relates to a process for preparing polymorphic form of Atorvastatin calcium, as depicted in Figure 1, which comprises the steps of:

a) adding aqueous calcium acetate solution to Atorvastatin sodium;

b) isolating the product obtained in step (a);

c) washing the wet cake with first solvent mixture of ethanol:water;

d) washing with second solvent of methyl tert-butyl ether;

e) washing finally with hot water; and

f) drying the product to obtain polymorphic form of Atorvastatin calcium as depicted in Figure 1.

The present invention also relates to a process to prepare polymorphic Form of Atorvastatin calcium, as depicted in Figure 1, which comprises addition of calcium acetate monohydrate solution, which is prepared by dissolving calcium acetate monohydrate in DM water at 20-30°C to the aqueous solution of Atorvastatin sodium at 55-60°C, the slurry is cooled to 40-42°C and stirred for 30 min. Filter the product and washed the obtained product first with 1:2 mixture of ethanol and DM water, followed by methyl t-butyl ether and finally with hot DM water.

The Atorvastatin sodium is prepared by the process known in the prior-art references.

POWDER X-RAY DIFFRACTION (PXRD) The X-ray powder diffractogram is obtained using a Seifert, XRD 3003 TT system. The X-ray generator was operated at 40 kv and 30 mA, using the Koc line of copper at 1.540598 A° as the radiation source. It is scanned in the diffraction range of 2.4 to 40 °28 at a scan rate of 0.03 °20 per second.
DIFFERENTIAL SCANNING CALORIMETRY (DSC)

The DSC curves were obtained using a Metller-Toledo thermal analysis system. The samples were heated from 30°C to 250°C at a heating rate of 10°C / min, in pierced aluminium crucibles.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE 1
PROCESS TO PREPARE POLYMORPHIC FORM OF ATORVASTATIN CALCIUM
STEP A: t-Butyl [(4R,6R)-[6-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenyl-
carbamoyl)pyirol-l-yl]ethyl]-2,2-dirnethyl-l,3-dioxan-4-yl] acetate (Diprotected Atorvastatin, 150 g) was suspended in a mixture of 10% w/w aqueous ethanol (3000 ml) and butylated hydroxyl toluene (0.45 g) and treated with 10% w/w aqueous hydrochloric acid (91.88 g) for 4 h at 40-45°C and then hydrolyzed with 10% w/w aqueous sodium hydroxide (241.67 g) at 18-20°C. After hydrolysis, the reaction mixture was treated with activated carbon (4.15 g), adjusted the pH to 12.0-12.5 with 10% w/w aqueous hydrochloric acid and concentrated at < 35°C under reduced pressure. The concentrated reaction mass was dissolved in a mixture of ethanol and DM water (1:5 v/v, 1800 ml), washed with tert-butylmethyl ether (2 x 600 ml), adjusted the pH to 9.0-9.5 with 10% w/w aqueous hydrochloric acid and obtained aqueous reaction mass of Atorvastatin sodium.

STEP B:

Calcium acetate monohydrate (26.24 g) was dissolved in DM water (600 ml) and added to the reaction mass of Atorvastatin sodium obtained in Step A, at 55-60°C. The slurry was cooled to 40-42°C and stirred for 30 min, filtered, washed with 1:2 mixture of ethanol and DM water (1200 ml) followed by MTBE (600 ml) and finally with hot DM water. The wet product was dried at 50-60°C till moisture content was achieved < 3% w/w to obtain title compound. Yield: 116.79 g; 88.24% HPLC Purity: 99.76%

EXAMPLE 2

PROCESS TO PREPARE POLYMORPHIC FORM OF ATORVASTATIN CALCIUM
STEP A:

t-Butyl [(4R,6R)-[6-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenyl-
carbamoyl)pyrrol-1 -yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl] acetate (Diprotected Atorvastatin, 135 g) was suspended in a mixture of 10% w/w aqueous ethanol (2700 ml) and butylated hydroxyl toluene (0.4 g) and treated with 10% w/w aqueous hydrochloric acid (82.68 g) for 4 h at 40-45°C and then hydrolyzed with 10% w/w aqueous sodium hydroxide (201.42 g) at 18-20°C. After hydrolysis, the reaction mixture was treated with activated carbon (4.05 g) adjusted the pH to 12.0-12.5 with 10% w/w aqueous hydrochloric acid and concentrated at < 35°C under reduced pressure. The concentrated reaction mass was dissolved in a mixture of ethanol and DM water (1:5 v/v, 1620 ml), washed with tert-butylmethyl ether (2 x 540 ml) and adjusted the pH to 9.0-9.5 with 10% w/w aqueous hydrochloric acid and obtained aqueous reaction mass of Atorvastatin sodium.

STEP B:

Calcium acetate monohydrate (23.62 g) was dissolved in DM water (540 ml) at 20-30°C and to the reaction mass of Atorvastatin sodium obtained in example-3, at 55-60°C. The slurry was cooled to 40-42°C and stirred for 30 min, filtered, washed with 1:2 mixture of ethanol and DM water (810 ml) followed by MTBE (540 ml) and finally with hot DM water. The wet product was dried at 60-70°C to obtain title product. Yield: 102.57 g; 86.11% HPLC Purity: 99.74%

WE CLAIM

1) Polymorphic form of Atorvastatin calcium of Formula I, as depicted in Figure 1,
which is having at least one of the following properties:

a) a powder X-ray diffraction pattern with reflections at about 2.78, 5.1, 7.8 ±0.2 °20 and broad diffraction intensity is observed in the range between 15and25°29;

b) a differential scanning calorimetry (DSC) endothermic peak at about 165-180°C.

2) A process for the preparation of polymorphic of Atorvastatin calcium of Formula I, as depicted in Figure 1, comprises:

a) adding aqueous calcium acetate solution to Atorvastatin sodium;

b) isolating the product obtained in step (a);

c) washing the wet cake with first solvent mixture of ethanol:water;

d) washing with second solvent of methyl tert-butyl ether;

e) washing finally with hot water; and

f) drying the product to obtain polymorphic form of Atorvastatin calcium as depicted in Figure 1.

3) A process for the preparation of polymorphic form of Atorvastatin calcium as depicted in Figure 1, claimed in claim 1 is substantially as herein described with reference to the examples.