FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13]
1. Title of the invention: "Process for the production of Atorvastatin calcium amorphous form"
2. Macleods pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 . Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai-400 059, Maharashtra, India.
3. The following specification particularly describes the invention and the manner in which it is to be performed


PROCESS FOR THE PRODUCTION OF ATORVASTATIN CALCIUM
AMORPHOUS FORM
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of amorphous atorvastatin calcium.
BACKGROUND OF THE INVENTION
Atorvastatin calcium is chemically known as [R-(R*R*]-2-(4-fluorophenyl)-pd-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1). It is disclosed in U.S. Patent No. 5,273,995 and represented by Formula I.
Ca

Atorvastatin calcium, 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 calcium (calcium Salt (2:1) trihydrate) is sold under the trade name LIPITOR®.
Atorvastatin calcium exists in various crystalline and amorphous forms. The amorphous form is of interest, due to its enhanced solubility as compared to crystalline forms, a higher solubility provide an improved bioavailability profile.
Processes for the preparation of amorphous atorvastatin calcium are disclosed in U.S.Patent Nos. 6,750,353; 6528660; 6087511; 6274740; 6613916; 6891047; 6646133; 7161012; 7151183; 7074940; 7208608; 7563911; 7230120 and 7189861, US Patent publication nos. 2005165242; 20060020137; 2006287538; 2006106230; 2006128971; 2007066835; 2007225353; 20080009540; 20080269314 and 20090182030, PCT application nos. WO 2005092852 and WO 2006048888.
US Patent publication no. 20090099371 describes a process for the preparation of amorphous atorvastatin calcium by evaporating a crude atorvastatin calcium solution in ethyl acetate, xylene, toluene or methyl isobutyl ketone solvents to afford crude amorphous Atorvastatin calcium as a foamy solid, which was isolated by adding an anti-solvent such as methyl t-butyl ether, cyclohexane, hexane, heptane, octane, isopropyl alcohol, diisopropyl ether, diethyl ether, or mixture thereof.
The processes hitherto reported for the preparation of amorphous atorvastatin calcium, lead to the preparation of a thermodynamically unstable product which degraded over the time in following impurities.

(1). Trans-5-(4-fluorophenyl)-l-(2-(4-hydroxy-6-oxo-tetrahydro-2H-pyran-2-yl) ethyl)-2-isopropyl-N, 4-diphenyl-lH-pyrrole-3-carboxamide compound of Formula II.

(2).Cis-2-(4-FluorophenyI)-β,δ-dihydroxy-5-(l -methyl ethyl)-3-phenyl-4-(phenyl amino) carbonyl-lH-pyrrole-1-heptanoic acid, methyl ester compound of formula III.


(3). 4-(4-Fluoro-phenyl)-2, 4-dihydroxy-2-isopropyl-5-phenyl-3, 6-dioxa-bicyclo [3.1.0]-hexane-l- carboxylic acid phenyl amide compound of formula IV.

(4). 2-(2-(4-fluorophenyl)-2-oxo-l-phenylethyIidene)-N-((E)-hexa-l, 3, 5-trien- 3-yl)-4-methyl-3-oxopentanamide compound of formula V.


(5). (4R, 6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-lH-pyrrol-l-yl) ethyl)-2, 2-dimethyl-l, 3-dioxane-4-yl) acetic acid compound of formula VI.

(6). [R-(R*, R*)]-2-(4-Fluorophenyl).β ,δ-D-5-(lMethy]ethyl)-3-phenyl-4-(phenyl amino) carbonyl]-1H-pyrrole- 1-heptanoic acid compound of formula VII.


(7). (3S, 5R)-7-[3-(phenylcarbamoyl)-2-isopropyl-4, 5-diphenyl-lH-pyrrol-l-yl]-3, 5-dihydroxy heptanoic acid compound of formula VIII

(8). (3S,5R)-7-[3-(phenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-lH-pyrrol-l-yl]-3,5-dihydroxy heptanoic acid compound of formula IX.

FORMULA IX
(9). (3R, 5R)-7-[3-(phenylcarbamoyl)-4, 5-bis (4-fluorophenyI)-2-isopropyl-lH-pyrrol-l-yl]-3, 5-dihydroxy heptanoic acid compound of formula X.


(10), 3-(4-Fluoro-benzoyl)-2-isobutyryl-3-diphenyl-oxirane-2-carboxylic acid phenyl amide compound of formula XI.

(11). 4-[Ib-(4-Fluoro-phenyl)-6-hydroxy-6-isopropyl-la-phenyl-6a-phenylcarbamoyl-hexahydro-1, 2-dioxa-5a-aza-cyclopropa[a]inden-3-yl]-3-(R)-hydroxy-butyric acid compound of formula XII.


(12). 4-[6-(4-Fluoro-phenyl)-6-hydroxy-lb-isopropyl-6a-phenyi-la-phenylcarbamoyl-hexahydro-1, 2-dioxa-5a-aza-cyclopropa[a]inden-3-yl]-3-(R)-hydroxy-butyric acid compound of formula XIII.

(13). (3R, 5R)-7-[3-(phenylcarbamoyl)-4, 5-bis (4-fluorophenyl)-2-isopropyl-lH-pyrrol-l-yI]-3, 5-dihydroxy heptanoic acid compound of formula XIV.
In light of the above drawbacks in the prior art processes, there is a need for the development of amorphous atorvastatin calcium, which is convenient to operate on an industrial scale, and gives thermodynamically stable product, which does not degrade during stability studies.

SUMMARY OF THE INVENTION
It is an objective of the present invention to provide an efficient process for the production of amorphous atorvastatin, which eliminates the problems of prior art and is convenient to operate on a commercial scale.
Accordingly, the present invention provides a process for the preparation of thermodynamically stable atorvastatin in an amorphous form which comprises suspending atorvastatin calcium in a methanol solvent, filtering and distilling the solvent to afford thermodynamically stable atorvastatin calcium in an amorphous form.
Major advantages of the present invention compared to the prior art processes are: i. Easy to operate on large-scale. ii. Reproducibly produces amorphous product having allowable levels of
residual solvents. iii. Reproducibly produces amorphous product having low levels of impurities. iv. Reproducibly produces thermodynamically stable amorphous product.
BRIEF DESCRIPTION OF THE FIGURE
Figure 1 is the X-ray powder diffraction pattern of amorphous atorvastatin calcium obtained by the present invention.
X-ray diffraction pattern were recorded using PANalytical X'Pert Pro Powder X-ray Diffractometer having 9- 0 configuration.

X-ray powder diffraction patterns show no peaks which are characteristic of a crystalline amorphous nature of the product and thus demonstrating the amorphous nature of the product of present invention.
DETAILED DESCRIPTION OF THE INVENTION
Atorvastatin calcium used as a starting material in the present invention and its intermediates may be prepared by any of the methods known in the art including those described in U.S. Patent Nos US RE40667; 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; 6,528,661; 6,600,051; 6,605,728; 6,777,560; 7,112,604; 7,122,681; 7414141 and 7557238 which are incorporated herein by reference only.
Atorvastatin calcium used as a starting material in the present invention may be present in a crystalline form or a mixture of amorphous and crystalline forms.
Atorvastatin calcium may be suspended in methanol solvent at a temperature in the range of 20°C to 55°C to afford a hazy atorvastatin solution.
The resulting hazy atorvastatin solution may be filtered through a celite bed at a temperature in the range of 20°C to 30°C to afford a clear atorvastatin solution.
The clear atorvastatin solution may be concentrated by distillation to afford thermodynamically stable atorvastatin calcium in an amorphous form.
The clear atorvastatin solution may be concentrated by distillation under reduced pressure at a temperature in the range of 25°C to 50°C.

Thermodynamically stable atorvastatin calcium in an amorphous form may be dried under reduced pressure at a temperature in the range of 50°C to 60°C.
Thermodynamically stable atorvastatin calcium in an amorphous form obtained by the present invention is substantially free from degradation impurities.
Thermodynamically stable atorvastatin calcium in an amorphous form obtained by the present invention is not degraded during stability studies.

In the following example, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
EXAMPLE:
PREPARATION OF THERMODYNAMICALLY STABLE ATORVASTATIN CALCIUM IN AN AMORPHOUS FORM
A suspension of R-(R*R*]-2-(4-fluorophenyl)-β,δ 5-dihydroxy-5-(l-methylethyl)-3-
phenyl-4-[(phenylamino) carbonyl]-lH-pyrrole-1-heptanoic acid tertiary butyl ester
(200 gm) in acetonitrile (100 ml) was treated with sodium hydroxide solution (22.14
gm sodium hydroxide dissolved in 350 ml water ) at 25 -30 °C for 15-20 minutes.
Water (400 ml) was added slowly in 1 hour and stirring was continued for 2 hours.
The solution of calcium chloride (61.46 gm calcium chloride dissolved in 350 ml
water) was added to the reaction mass very slowly over 1 hour at 50-55°C to afford
the precipitation of atorvastatin calcium. The precipitated mass was diluted with
water (1.5 litres), stirred at 25 to 30°C for 3 hours, filtered and washed with water
(1000 ml) to get wet atorvastatin calcium. The wet atorvastatin calcium was dried at
55-60°C and then this dried atorvastatin calcium (200 gm) was suspended in
methanol (5 liters) and stirred at 25 -30 °C for 1 hour. The resulting hazy solution
was filtered and the filtrate obtained was concentrated by distillation under reduced
pressure to afford thermodynamicaUy stable atorvastatin calcium in an amorphous
form.
Yield: 120 gm
Purity: 99.6% (By HPLC)
Purity after six month stability: 99.6% (By HPLC)

WE CLAIM:
1. A process for the preparation of thermodynamically stable atorvastatin in an amorphous form which comprises suspending atorvastatin calcium in a methanol solvent, filtering and distilling the solvent to afford thermodynamically stable atorvastatin calcium in an amorphous form.
2. The process according to claim 1, wherein atorvastatin calcium is suspended in methanol solvent at a temperature in the range of 20°C to 55°C to afford a hazy atorvastatin solution.
3. The process according to claims 1 and 2, wherein resulting hazy atorvastatin solution is filtered through a celite bed.
4. The process according to claims 1 and 3, wherein resulting hazy atorvastatin solution is filtered at a temperature in the range of 20°C to 30°C to afford a clear atorvastatin solution.
. 5. The process according to claim 4, wherein clear atorvastatin solution is concentrated by distillation to afford thermodynamically stable atorvastatin calcium in an amorphous form.
6. The process according to claim 5, wherein clear atorvastatin solution is
concentrated by distillation under reduced pressure at a temperature in the range of
25°C to 50°C.
7. The process according to claims 1 and 5, wherein thermodynamically stable
atorvastatin calcium in an amorphous form is dried under reduced pressure at a
temperature in the range of 50°C to 60°C.

8. The process according to claims 1 and 7, wherein thermodynamic ally stable
atorvastatin calcium in an amorphous form is substantially free from degradation
impurities.
9. The process according to claims 1, 7 and 8 wherein thermodynamically stable
atorvastatin calcium in an amorphous form is not degraded during stability studies.
10. A process for the preparation of thermodynamically stable atorvastatin calcium in
an amorphous form as herein described in specification and example.

Dated this 06th day of November 2009
Signature: Name: Dr. Rajendra Agarwal