FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
A NOVEL POLYMORPHIC FORM W-XII' OF ATORVASTATIN
CALCIUM AND HYDRATES THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a novel polymorphic form 'W-XII' of atorvastatin calcium and hydrates thereof and process for its preparation. The invention further relates to pharmaceutical compositions that include the Form 'W-XII' of atorvastatin calcium and hydrates thereof and one or more pharmaceutical^ 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-XII' of atorvastatin calcium and hydrates thereof and process for its preparation. The invention further relates to pharmaceutical compositions that include the form 'W-XII' of atorvastatin calcium and hydrates thereof and one or more pharmaceutical^ 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-[(phenyl amino) 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,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; 2006106232 and 20070066678.
The present inventors have now developed atorvastatin calcium and hydrates thereof in a novel polymorphic form referred as polymorphic form 'W-XII', which is stable, consistently reproducible and useful to make pharmaceutical compositions. It was surprisingly found that when the atorvastatin sodium suspension is treated with calcium acetate solution, atorvastatin calcium and hydrates thereof is obtained in a novel polymorphic form 'W-XII' when dried at room temperature followed by further drying at high temperature.
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-XII'.
Embodiments of the polymorphic form 'W-XII' and hydrates thereof may include one or more of the following features. For example, the polymorphic Form 'W-XII' 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 2.8, 7.8 ± 0.2 20. Powder X-ray diffraction pattern reported herein was determined by Rigaku X-Ray diffractometer model no. 2200-v.
The crystalline form 'W-XII' 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-XII' 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-XII' of atorvastatin calcium and hydrates thereof. The process includes:
a) treating atorvastatin sodium suspension with calcium acetate solution,
b) isolating the form 'W-XII' of atorvastatin calcium and hydrates thereof from the reaction mixture by drying the product at room temperature followed by further drying at high temperature.
The starting material atorvastatin sodium is obtained by converting atorvastatin calcium Form I which may be in turn obtained by any process known in the art for example as reported in U.S. patent No. 5, 969,156. The process involves following steps.
The solution of atorvastatin calcium Form I was obtained by adding atorvastatin calcium Form I in a water. This solution of atorvastatin calcium Form-I is added with hydrochloric acid. To the reaction mixture halogenated solvent such as dichloromethane is added. Organic layer is separated and treated with sodium


hydroxide. The reaction mixture is stirred for 2-4 hours and filtered and atorvastatin sodium is isolated.
The atorvastatin sodium suspension was prepared in water. In the clear solution of calcium acetate in water was added atorvastatin sodium suspension and stirred for 15 minutes at 45-50°C. The reaction mixture is heated to about 60-70°C and stirred for 30 minutes. Reaction mixture is cooled to 50°C and filtered. The solid obtained was dried at room temperature for 12-14 hours and further dried at 60°C for 14-16 hours to get form 'W-XII' of atorvastatin calcium and hydrates thereof from the reaction mixture.
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 atorvastatin sodium and hydrates thereof:
Atorvastatin calcium Form I (5.0 g) was added in water (100 ml) and stirred. To the reaction mixture was added hydrochloric acid (1.5 ml) at room temperature. Dichloromethane (100 ml) was added to the reaction mass. Organic layer was separated, cooled to 0-5°C and added with sodium hydroxide (50 %, 1.5 ml). The reaction mixture was maintained for 2-3 hours under stirring at same temperature. The solid was filtered and dried at 55-60°C to get atorvastatin sodium and hydrates thereof. Yield: 5.2 g
Preparation of atorvastatin calcium and hydrates thereof:
Calcium acetate (0.8 g) was added in water (30 ml) with stirring and heated to 45-50°C. Clear solution was obtained. To this, suspension of atorvastatin sodium (5.0 g) in water (100 ml) was added and stirred for 10 minutes. The temperature


of reaction mixture was raised to 65-70 C and stirred for 30 minutes. The reaction mixture was cooled to 50°C, filtered and the solid was dried at was dried at room temperature for 12-14 hours and further dried at 60°C for 14-16 hours to get form 'W-XII' of atorvastatin calcium and hydrates thereof.


WE CLAIM:
1. Polymorphic form 'W-XII' of atorvastatin sodium and hydrates thereof.
2. A polymorphic form 'W-XII' of atorvastatin sodium and hydrates thereof characterized by a powder X-ray diffraction pattern having the peaks at 2.8, 7.8 ±0.2° 20.
3. A process for the preparation of a polymorphic Form 'W-XII' of atorvastatin calcium and hydrates thereof, the process comprising
a. treating atorvastatin sodium suspension with calcium acetate
solution,
b. isolating the form 'W-XII' of atorvastatin calcium and hydrates
thereof from the reaction mixture by drying the product at room
temperature followed by further drying at high temperature.
4. The process of claim 3, wherein the suspension of atorvastatin sodium is prepared in water.
5. The process of claim 3, wherein the solution of calcium acetate is prepared in water.
6. The process of claim 3, wherein the drying is carried out at room temperature for 12-14 hours and further dried at 60°C for 14-16 hours to get form 'W-XII' of atorvastatin calcium and hydrates thereof
7. A pharmaceutical composition comprising a polymorphic form 'W-XII' and hydrates thereof of atorvastatin calcium and one or more pharmaceutically acceptable carriers, excipients or diluents.


8. A polymorphic Form 'W-XII' of atorvastatin calcium and hydrates thereof of claim 1,2,3 and 5 contains 0 to 4 moles of water.

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