FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(Sec section 10 and rulel3)
1. TITLE OF THE INVENTION:
A NOVEL POLYMORPHIC FORM 'W-V 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-V of atorvastatin calcium and hydrates thereof and process for its preparation. The invention further relates to pharmaceutical compositions that include the Form 'W-V 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-V of atorvastatin calcium and hydrates thereof and process for its preparation. The invention further relates to pharmaceutical compositions that include the Form 'W-V 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)-3,5-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)-(3,5-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-V, which is stable, consistently reproducible and useful to make pharmaceutical compositions. It was surprisingly found that when the atorvastatin calcium polymorphic form-l is treated with an ethanol-water mixture, gradually cooled to 50-55°C and dried for 4-6 hours, it is converted in a novel polymorphic form 'W-V.
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-V.
Embodiments of the polymorphic Form 'W-V and hydrates thereof may include one or more of the following features. For example, the polymorphic Form 'W-V 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 8.0 (singlet) and 23.9 ± 0.2° 2G. Powder X-ray diffraction pattern reported herein was determined by Rigaku X-Ray diffractometer model no. 2200-v.
The Form 'W-V 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-V and hydrates thereof of atorvastatin calcium and one or more pharmaceutically 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-V of atorvastatin calcium and hydrates thereof. The process includes:
a) providing solution of atorvastatin calcium Form I in a suitable solvent mixture,
b) gradually cooling the solution of step a) to 45-50°C,
c) isolating the Form 'W-V of atorvastatin calcium and hydrates thereof from the reaction mixture thereof.
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 heating atorvastatin calcium Form I in a suitable solvent mixture for 1 hour. Suitable temperatures for preparing the solution of atorvastatin calcium Form-I is below 80 °C. The reaction mixture is then cooled gradually to 45-55°C and further added with suitable solvent mixture. The reaction mass is further stirred for 14-16 hours at room temperature.


Suitable solvent mixture includes mixture of water and water miscible solvent. Water miscible solvent, which may be used in the process, includes but are not limited to alcohols including methanol, ethanol, isopropyl alcohol, n-butanol, tertiary butyl alcohol and the like. The ratio of solvent to water used is 5:1.
To enhance crystallization, the reaction mass may be further maintained at temperatures lower than 40 °C for complete crystallization of the product. The exact cooling temperature and time required for complete crystallization may be readily determined by a person skilled in the art.
Form 'W-V of atorvastatin calcium and hydrates thereof may be isolated from the final mixture, with or without cooling below the crystal formation temperature. 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 at about 40°C to 80°C for about 4 hours.
In yet another aspect of the present invention there is provided polymorphic Form 'W-V of atorvastatin calcium and hydrates thereof in high purity of 99.0% or more when measured by HPLC.
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-V ‘ of atorvastatin calcium and hydrates thereof.
Atorvastatin calcium Form I (50.0 g) was suspended in a mixture of ethanol (650.0 ml) and water (150.0 ml) and heated to reflux for 1 hour. The mixture was then gradually cooled to 50-55°C. A mixture of ethanol (650.0 ml) and water (150.0 ml) further added to reaction mixture obtained thereof and stirred for 16 hours at room temperature. The solid was collected and dried at 65 °C for 4 hours to get Form 'W-V of atorvastatin calcium and hydrates thereof. Yield: 42.3 g HPLC purity: 99.5 %


WE CLAIM:
1. Polymorphic Form 'W-V of Atorvastatin calcium and hydrates thereof.
2. A polymorphic Form 'W-V of atorvastatin calcium and hydrates thereof characterized by a powder X-ray diffraction pattern having the peaks at 8.0 (singlet) and 23.9 ± 0.2° 20.
3. A process for the preparation of a polymorphic Form 'W-V of atorvastatin calcium and hydrates thereof, the process comprising

a) providing solution of atorvastatin calcium Form I in a suitable solvent mixture,
b) gradually cooling the solution of step a) to 45-50°C,
c) isolating the Form 'W-V of atorvastatin calcium and hydrates thereof from the reaction mixture thereof.

4. The process of claim 3, wherein the suitable solvent mixture is a mixture of water and water miscible solvent.
5. The process of claim 4, wherein the water miscible solvent includes but not limited to alcohols including methanol, ethanol, isopropyl alcohol, n-butanol, tertiary butyl alcohol and the like.
6. The process of claim 3, wherein the solution of atorvastatin calcium Form I in suitable solvent mixture is prepared by heating below 80 °C.
7. The process of claim 3 wherein isolating the Form 'W-V of atorvastatin calcium and hydrates thereof from the reaction mixture thereof is carried out by drying at 60-70°C.


8. A pharmaceutical composition comprising a polymorphic Form 'W-V and hydrates thereof of atorvastatin calcium and one or more pharmaceutically acceptable carriers, excipients or diluents.
9. A polymorphic Form 'W-V of atorvastatin calcium and hydrates thereof having the purity of 99.0 % or more.
10. A polymorphic Form 'W-V of atorvastatin calcium and hydrates thereof of claim 1, 2, 3, 8 and 9 contains 0 to 4 moles of water.

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