FIELD OF THE INVENTION

The present invention relates to a novel process for the preparation of crystalline Atorvastatin calcium Form-I.

BACKGROUND OF THE INVENTION

Atorvastatin, ([R-(R*, R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino) carbonyl]-lH-pyrrole-l-heptanoic acid), marketed in the form of its calcium salt, a synthetic HMG-CoA reductase inhibitor, is used for the treatment of hyperlipidemia and hypercholesterolemia, both of which are risk factors for arteriosclerosis and coronary heart disease.

Atorvastatin in its calcium form, i.e. bis[R-(R*, R*)]-2-(4-fIuorophenyl)-β,δ-dihydroxy- 5-(l-methylethyl)-3- phenyl-4-[(phenylamino) carbonyl]-lH-pyrrole-l-heptanoic acid calcium salt having formula I is more suitable for developing formulations and has been recommended as a drug.

Atorvastatin hemi-calcium salt trihydrate is marketed under the name LIPITOR in the form of tablets, which contains 10, 20, or 40 mg atorvastatin, by Warner-Lambert Co.

Atorvastatin was first disclosed and generically claimed in U. S. Patent No. 4,681,893.

United States reissue patent no. RE 40667 E of Patent no. US 5,273,995 claims hemi calcium salt of atorvastatin specifically in its claim 6. It also describes pharmaceutical compositions comprising atorvastatin calcium and their use in the treatment of hypercholesterolemia

Processes for preparing atorvastatin-and its hemi-calcium salt are also disclosed in U.S. Pat. Nos, 5,273,995; 5,298,627; 5,003,080; 5,097,045; 5,124,482; 5,149,837; 5,216,174; 5,245,047, 5,280,126, which are incorporated hereby references,

U.S. Patent No. 5,969,156 discloses atorvastatin calcium crystalline Form I, Form II, Form IV and process for their preparation.

U.S. Patent applications No. U,S, 2002/0183378 A1 and U.S. 2003/0212279 discloses process for the preparation of crystalline Atorvastatin calcium Form-I from Atorvastatin calcium crystalline forms Form-V, VII. VIII, IX and X. U.S 20070032665 A1 discloses process for the preparation of crystalline Atorvastatin calcium Form-I by adding water to the solution comprising of Atorvastatin and alcohol. The Atorvastatin calcium Form-I obtained by the above prior art processes is having less purity and yield.

There is a continuous need to prepare crystalline Atorvastatin Form-I having high yield and purity.

Thus the present invention discuss about cost effective and commercially viable process for the preparation of crystalline Atorvastatin Form--I having high yield and purity.

OBJECT AND SUMMARY OF THE INVENTION

The principle object of the present invention is to provide an improved process for the preparation of crystalline Atorvastatin calcium Form-I comprising the steps of: a) suspending crystalline Atorvastatin calcium in water; b) heating the suspension to reflux; c) cooling the solution; and d) isolating crystalline Atorvastatin calcium Form-I Another object of the present invention is to provide an improved process for the preparation of crystalline Atorvastatin calcium Form-I comprising the steps of: a) suspending crystalline Atorvastatin calcium in a mixture of water and alcohol; b) seeding with Atorvastatin calcium Form-I; c) optionally heating the suspension; and d) isolating crystalline Atorvastatin calcium Form-I.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates Powdered X-ray diffraction pattern of Atorvastatin calcium Form-M.

Figure 2 illustrates Powdered X-ray diffraction pattern of Atorvastatin calcium Form-I.

Instrumentation

Powder X-ray Diffraction (PXRD)

The said polymorphs of the present invention are characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorphs of the invention were measured on PANalyticaly 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 2.0º-50.0°, 0.030º step size and 50 seconds step time.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the process for the preparation of crystalline Atorvastatin calcium Form-I by suspending any crystalline form of Atorvastatin in water or mixture of water and water miscible organic solvent and isolating Form I of Atorvastatin Calcium.

In one aspect, the present invention provides process for the preparation of crystalline Atorvastatin calcium Form-I comprising the steps of:

a) suspending crystalline Atorvastatin calcium in water;
b) heating the suspension;
c) cooling the reaction mass; and
d) isolating crystalline Atorvastatin calcium Form-I.

According to one embodiment of the present invention, crystalline Atorvastatin calcium used in step a) is crystalline Atorvastatin calcium, preferably Form-M which is claimed in WO 2007/096903.

According to another embodiment of the present invention, the suspension is heated to 60-110 preferably 70-110 more preferably 80-100

According to one more embodiment of the present invention, the reaction mass is cooled to 10-45 preferably 25-35 ºC.

As per the present invention, Atorvastatin Calcium Form-M can be prepared according to the procedures described in WO 2007/096903. Form M of Atorvastatin Calcium is suspended in DM water and refluxed for 1-5 hours, preferably 2-3 hrs. Reaction mass is cooled to 10-45 preferably 25-35 °C and Atorvastatin Calcium Form I is isolated.

In another aspect, the present invention provides process for the preparation of crystalline Atorvastatin calcium Form-I comprising the steps of:

a) suspending crystalline Atorvastatin calcium in a mixture of water and alcohol;
b) seeding with Atorvastatin calcium Form-I;
c) optionally heating the suspension; and
d) isolating crystalline Atorvastatin calcium Form-I.

According to one embodiment of the present invention, crystalline Atorvastatin calcium used in step a) is crystalline Atorvastatin calcium, preferably Form-M which is claimed in WO 2007/096903,

As per the present invention, Form M of Atorvastatin Calcium is suspended in mixture of water and alcohol and seeded with Atorvastatin Calcium Form 1. Alcohol used in the above step is selected from methanol, ethanol, propanol, isopropyl alcohol, preferably methanol. The reaction mass is optionally heated to 35-50 ''C, preferably 35-40 °C for 15-30 hours, preferably 16-20 hours and Atorvastatin Calcium Form I is isolated.

In one more aspect, the present invention provides a pharmaceutical composition that includes a therapeutically effective amount of Atorvastatin Calcium Form I prepared according to the processes of the present invention and one or more pharmaceutically acceptable carriers, percipients or diluents.

Accordingly, the pharmaceutical composition comprising Atorvastatin Calcium Form I along with one or more pharmaceutically acceptable carriers of this invention may further be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions, and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. The compositions may be prepared by direct blending, dry granulation, or wet granulation or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients.

Thus the advantage lies in utilizing Atorvastatin Calcium Form-M for the preparation of Atorvastatin Calcium Form-I, thereby making the process cost-effective and enhances the purity of Atorvastatin Calcium Form-I.

The following non-limiting example illustrates specific embodiments of the present invention. The example, not intended to be limiting the scope of present invention in any way.

Experimental procedure Example 1

Atorvastatin calcium Form-M (10 gm), which was prepared by the process described in WO 2007/096903, suspended in DM water (100 ml) and the reaction mass was refluxed for two hours and then cooled to 25 The reaction mass was filtered and dried to yield Atorvastatin Calcium Form-I (8 gm)

Example 2

Atorvastatin calcium Form-M (10 gm), which was prepared by the process described in WO 2007/096903, suspended in DM water (170 ml) and Methanol (30 ml) and seeded with 0.5 gm of Atorvastatin Calcium Form-I. The reaction mass was stirred at RT for 16- 20 hours. The reaction mass was filtered and dried to yield Atorvastatin Calcium Form-I
(8 gm).

Example 3

Atorvastatin calcium Form-M (10 gm), which was prepared by the process described in WO 2007/096903, suspended in DM water (170 ml)/ 30 ml Methanol and seeded with 0.5 gm of Atorvastatin Calcium Form-I. The reaction mass was stirred at 40 °C for 16-20 hours and then cooled to 25 ºC. The reaction mass was filtered and dried to yield Atorvastatin Calcium Form-I (8 gm).

We claim:

1. A process for the preparation of crystalline Atorvastatin calcium Form-I comprising the steps of:
a) suspending crystalline Atorvastatin calcium in water;
b) heating the suspension;
c) cooling the reaction mass; and
d) isolating crystalline Atorvastatin calcium Form-1.

2. The process according to claim 1, wherein the crystalline Atorvastatin calcium is Atorvastatin calcium Form-M,

3. The process according to claim 1, wherein the suspension is heated to a temperature of 60-100 °C.

4. The process according to claim 1, wherein the reaction mass is cooled to 10-45

5. A process for the preparation of crystalline Atorvastatin calcium Form-1 comprising the steps of:

a) suspending crystalline Atorvastatin calcium in a mixture of water and alcohol;
b) seeding with Atorvastatin calcium Form-I;
c) optionally heating the suspension; and
d) isolating crystalline Atorvastatin calcium Form-I.

6. The process according to claim 5, wherein the crystalline Atorvastatin calcium is Atorvastatin calcium Form-M.

7. The process according to claim 5, wherein the alcohol is selected from methanol, ethanol, propanol or isopropyl alcohol.

8. Atorvastatin calcium Form-I obtained by any of the claims 1-7.

9. A pharmaceutical composition comprising the Atorvastatin calcium Form-I obtained by any of the claims 1-7,