FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(Sec section 10 and rule 13)
1. TITLE OF THE INVENTION:
A NOVEL POLYMORPHIC FORM 'W-Y-IF OF ATORVASTATIN CALCIUM AND HYDRATES THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a novel polymorphic Form 'W-ll' of atorvastatin calcium and hydrates thereof and process for its preparation. The invention further relates to pharmaceutical compositions that include the Form 'W-ll' of atorvastatin calcium and hydrates thereof and one or more pharmaceutically acceptable carriers, excipients or diluents.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention provides a novel polymorphic Form 'W-ll' of atorvastatin calcium and hydrates thereof and process for its preparation. The invention further relates to pharmaceutical compositions that include the Form 'W-ll' of atorvastatin calcium and hydrates thereof and one or more pharmaceutically acceptable carriers, excipients or diluents.
Atorvastatin calcium of formula-l is known by the chemical name [R-(R*, R*)]-2-
(4-fluorophenyl)-(b,d- dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)
carbonyl]-1H-pyrrole-1-heptanoic acid hemi-calcium salt (2:1) trihydrate. The hemi-calcium salt of atorvastatin is useful as an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and is thus useful as a hypolipidemic and hypocholesterolemic agent.

U.S. Patent No. 4,681,893, disclosed certain trans-6-[2-(3- or 4-carboxamido-substituted-pyrrol-1-yl)alkyl]-4-hydroxy-pyran-2-ones including trans (±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[(2-tetrahydro- 4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.
U.S. Patent No. 5,273,995, disclosed the enantiomer having the R form of the ring-opened acid of trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[(2-tetrahydro-4 -hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1 H-pyrrole-3-carboxamide, i.e., [R-(R*,R*)]-2-(4-fluorophenyl)-p,6-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenyl amino)carbonyl]-1H-pyrrole-1-heptanoic acid which is atorvastatin.


U.S. Patent Nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,397,792; 5,342,952;
5,298,627; 5,446,054; 5,470,981; 5.489,690; 5,489,691; 5,510,488; 5,998,633; and 6,087,511 discloses various processes and key intermediates for preparing atorvastatin and its salts.
U.S. Patent Nos. 5,969,156 and 6,121,461 discloses Crystalline Forms I, II, III and IV of atorvastatin hemi-calcium.
Several polymorphs have been reported related to atorvastatin or its salts and hydrates for example, in U.S. Patent Nos. 6,605,636; 6,992,194; 7,122,681; 7,144,916; 7,074,818; PCT application nos. WO 2002057229; WO 2006048894; WO 2006067795; WO 2006106372; WO 2006021216 and U.S.Application Nos. 2006205805;2006122403; 2006063826;2006106231 and 2006106232.
The present inventors have now developed atorvastatin calcium and hydrates thereof in a novel polymorphic form referred as polymorphic form 'W-ll', which is stable, consistently reproducible and useful to make pharmaceutical compositions. It was surprisingly found that when the atorvastatin calcium polymorphic form-l solution is treated with base, it is converted in a novel polymorphic form 'W-ll'.
In one of the aspect of the present invention there is provided atorvastatin calcium and hydrates thereof in a novel polymorphic form referred as polymorphic form 'W-ll'.
Embodiments of the polymorphic Form 'W-ll' and hydrates thereof may include one or more of the following features. For example, the polymorphic Form 'W-ll' of atorvastatin calcium and hydrates thereof may be characterized by a powder X-ray diffraction pattern as depicted in figure I, having the peaks at 7.6 and 18.9 ± 0.2° 20. Powder X -ray diffraction pattern reported herein was determined by Rigaku X-Ray diffractometer model no. 2200-v.

The polymorphic Form 'W-ll' of atorvastatin calcium and hydrates thereof may contain 0 to 4 moles of water.
In yet another aspect of the present invention provides a pharmaceutical composition comprising a polymorphic Form 'W-ll' and hydrates thereof of atorvastatin calcium and one or more pharmaceutical^ acceptable carriers, excipients or diluents. Pharmaceutical composition of present invention includes but not limited to solid oral, liquid or injectable dosage form.
In yet another aspect of the present invention there is provided a process for the preparation of a polymorphic Form 'W-ll' of atorvastatin calcium and hydrates thereof. The process includes:
a) combining atorvastatin calcium Form I solution with a base,
b) isolating the Form 'W-ll' of atorvastatin calcium and hydrates thereof from the reaction mixture.
The starting material atorvastatin calcium Form I may be obtained by any process known in the art for example as reported in U.S. patent No. 5, 969,156. The solution of atorvastatin calcium Form I was obtained by adding atorvastatin calcium Form I in tetrahydrofuran followed by addition of antioxidant such as butylated hydroxy toluene or butylated hydroxy anisole. The reaction mixture is stirred at room temperature to get clear solution and filtered through Hyflow. To the reaction mixture obtained thereof, aqueous ammonia solution (25 %) is added and further stirred for additional 30-40 minutes at room temperature.
Form 'W-ll' of atorvastatin calcium and hydrates thereof may be isolated from the final mixture, with or without cooling. Isolation techniques such as filtration by gravity, or by suction, centrifugation, and the like may be employed.


The wet solid obtained is dried under normal or reduced pressure. For example, drying may be performed under reduced pressure or under atmospheric pressure at a temperature of about 40 °C to 80 °C.
The present invention is further illustrated by the following example which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example
Preparation of polymorphic form 'W-ll' of atorvastatin calcium and hydrates thereof.
Atorvastatin calcium Form I (5.00 g) was added in tetrahydrofuran (12.5 ml) and immediately added butylated hydroxy anisole (25 mg). The reaction mixture was stirred at room temperature. The mass was filtered through Hyflow and washed with tetrahydrofuran. The reaction mixture obtained thereof was then added to aqueous ammonia solution (75.0 ml, 25 %) and further stirred for 60-90 minutes. The solid was filtered and dried at 60°C to get Form 'W-ll' of atorvastatin calcium and hydrates thereof. Yield: 3.8 g


WE CLAIM:
1. Polymorphic Form 'W-ll' of Atorvastatin calcium and hydrates thereof.
2. A polymorphic Form 'W-ll' of atorvastatin calcium and hydrates thereof characterized by a powder X-ray diffraction pattern as depicted in figure I, having the peaks at 7.6 and 18.9 ± 0.2° 20.
3. A process for the preparation of a polymorphic Form 'W-ll' of atorvastatin
calcium and hydrates thereof, the process comprising
a) combining atorvastatin calcium Form I solution with a base,
b) isolating the Form 'W-ll' of atorvastatin calcium and hydrates thereof from the reaction mixture thereof.

4. The process of claim 3, wherein the solution of atorvastatin calcium Form I is prepared by addition of tetrahydrofuran and an antioxidant.
5. The process of claim 4 wherein antioxidant is butylated hydroxy anisole.
6. The process of claim 3, wherein the base is aqueous ammonia solution.
7. A pharmaceutical composition comprising a polymorphic Form 'W-ll' and hydrates thereof of atorvastatin calcium and one or more pharmaceutical^ acceptable carriers, excipients or diluents.
8. A polymorphic Form 'W-ll' of atorvastatin calcium and hydrates thereof of claim 1,2,3 and 7 contains 0 to 4 moles of water.


6

ABSTRACT
The present invention provides a novel polymorphic Form 'W-ll' of atorvastatin calcium and hydrates thereof and process for its preparation. The invention further relates to pharmaceutical compositions comprising Form 'W-ll' of atorvastatin calcium and hydrates thereof and one or more pharmaceutically acceptable carriers, excipients or diluents.