FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
As amended by the Patents (Amendment) Act, 2005
&
The Patents Rules, 2003
As amended by the Patents (Amendment) Rules, 2005
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
A process of preparing amorphous atorvastatin calcium
INVENTORS
Names : 1) Gupte Raj an Vitthal
2) Hire Chandrabhan Madhav
3) Bhendkar Amol Haridas Nationality : all Indian Nationals
Address : Kopran Research Laboratories Limited D-28/2, TTC Industrial Area, MIDC Turbhe, Navi Mumbai - 400705, Maharashtra, India
APPLICANTS
Name : KOPRAN RESEARCH LABORATORIES LTD
Nationality: Indian Company
Address : Parijat House, 1076 Dr E Moses Road, Worli,
1 Mumbai 400018, Maharashtra, India

PREAMBLE TO THE DESCRIPTION

The following specification particularly describes the nature of this invention and the
manner in which it is to be performed:

Technical field
The present invention relates to a process of preparing amorphous atorvastatin calcium.
Particularly the present invention relates to a process of preparing amorphous atorvastatin calcium from crystalline atorvastatin sodium without forming crystalline atorvastatin calcium.
The present invention also relates to amorphous atorvastatin calcium prepared by the process of the invention.
Background of Invention :
Atorvastatin is known by the chemical name [R-(R*, R*)]-2-(4-Fluorophenyl)-P,8-dihydroxy-5-( 1 -methylethyl)-3-phenyl-4-[(phenylamino)carbonyl] -1 H-pyrrole-1 -heptanoic acid. Atorvastatin in its calcium salt form, i.e. [R-(R*, R*)]-2-(4-Fluorophenyl)-P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole-1-heptanoic acid calcium salt having the formula (1)
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Ca2+

is useful as inhibitor of the 3-hydroxy-3-methyl-glutamine co-enzyme A reducing enzyme. Therefore, atorvastatin calcium salt is a valuable lipid lowering agent and used as drug for hyperlipidemia and hyper cholestrolemia.
Atorvastatin used in the pharmaceutical compositions is usually in the form of crystalline atorvastatin calcium though amorphous atorvastatin calcium is also being used recently. Amorphous atorvastatin calcium is convenient to be formulated. Dissolution characteristics and bioavailability of amorphous atorvastatin calcium over the crystalline form of atorvastain calcium are disclosed in Chem Pharma bulk, 38, 2003-7, 1990 by Kohno T.
US 5,003,080, US 5,097,045, US 5,103,024, US 5,124,482, US 5,149,837, US 5,155,251, US 5,216,714, US 5,245,047, US 5,248,793, US 5,280,126, US 5,397,792, and US
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5,342,952, which are herein incorporated by reference, disclose various processes and key intermediates for preparing atorvastatin calcium. The processes reported in the prior art give a mixture of crystalline and amorphous forms of atorvastatin calcium and involve elaborate purification procedures for separation thereof, as the crystalline and amorphous atorvastatin calcium are interconvertible. This also makes the processes unsuitable for large-scale production of amorphous atorvastatin calcium.
US 6,087,511, US 6,274,740 and WO 97/03960 relate to preparation of amorphous atorvastatin calcium comprising dissolving crystalline atorvastatin calcium in a non-hydroxylic solvent and removing the solvent by vacuum drying for several days (3 to 7 days) at high temperature. Exposure of the material to high temperature for several days leads to degradation of the product. Slow removal of solvents also makes the process very inconvenient to operate at a large scale besides reducing yield.
International applications WO02/083637 and WO02/083638 disclose the preparation of amorphous atorvastatin calcium comprising treating methanolic solution of diol protected tert-butyl ester of atorvastatin in the presence of an aqueous acid; adding aqueous hydroxide solution to the reaction mixture and removing unreacted diol protected tert-butyl ester by solvent extraction; treating the product obtained with calcium chloride solution to obtain crude amorphous atorvastatin calcium salt; isolating crude calcium salt; treating the crude product so isolated with activated carbon in aqueous ethyl acetate; recovering the product by addition of non polar hydrocarbon solvent followed by filtration and drying to produce pure amorphous atorvastatin, calcium. The amorphous
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atorvastatin calcium formed by the above process needs extensive purification as the reaction sequence carries with it impurities like unreacted reactants and as the atorvastatin sodium formed, as an intermediate, is not isolated.
International application WO 03/018547 discloses a process to prepare amorphous atorvastatin calcium without isolating crystalline atorvastatin calcium by treating atorvastatin lactone with aqueous solution of alkali or alkaline earth metal hydroxide, extracting the atorvastatin calcium with organic solvent like halogenated hydrocarbons, aliphatic esters or aromatic hydrocarbons followed by adding an organic anti-solvent like ether or non polar hydrocarbon to precipitate the amorphous atorvastatin calcium without isolating crystalline atorvastatin calcium. Alternatively amorphous atorvastatin calcium is prepared from crystalline atorvastatin calcium by dissolving the crystalline form in an organic solvent, distilling off the solvent partially and adding anti-solvent to precipitate amorphous form.
WO 2004/085391 discloses a process for the synthesis of amorphous atorvastatin calcium from the amino salt of atorvastatin acid like L-lysine salt of atorvastatin or L-arginine salt of atorvastatin. This process requires preparation of basic amino salts of atorvastatin by treating atorvastatin acid with basic amino acid.
WO2005/005384 describes in-situ preparation of amorphous atorvastatin calcium and hydrates thereof from atorvastatin tert-butyl ester. In this process atorvastatin sodium formed as an intermediate is not isolated and purified before being converted it into
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amorphous atorvastatin calcium salt. The final product need to be purified using extensive and elaborate purification techniques.
Some of the prior art processes give a mixture of crystalline and amorphous atorvastatin calcium, which are interconvertible and therefore difficult to be separated and filtered. Sodium salt of atorvastatin is not generally isolated and purified in the prior art processes. As a result impurities are carried forward in the reaction sequence requiring extensive purification of the final product amorphous atorvastatin calcium. Besides yield and purity of amorphous atorvastatin are also adversely affected. Impurities present in atorvastatin calcium as reported in the literature [Journal of Pharmaceutical & Biomedical Analysis, 33(5), 1017-1023, 2003; Rapid communications in Mass Specrometry, 13(11), 1003-1015, 1999] include lactone forms of atorvastatin, desfluroatorvastatin or distereoisomer of atorvastatin and also unknown impurities. Amorphous atorvastatin calcium being not soluble in most of the organic solvents, it requires extensive and elaborate purification procedures as compared to the intermediates. This increases the purification time and cost and renders the purification step quite tedious and cumbersome.
Objects of the invention :
An object of the invention is to provide a process for the preparation of amorphous atorvastatin calcium from crystalline atorvastatin sodium without forming crystalline atorvastatin calcium.
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Another object of the invention is to provide a process for the preparation of amorphous atorvastatin calcium in high purity and good yield.
Another object of the invention is to provide a process for the preparation of amorphous atorvastatin calcium, which is simple, easy and convenient to carry out, and is economical.
Another object of the invention is to provide a process for the preparation of amorphous atorvastatin calcium, which reduces the process duration and prevents degradation of the product and renders the process suitable for plant scale manufacture.
Detailed Description of Invention:
According to the invention there is provided a process of preparing amorphous
atorvastatin calcium comprising the following steps :
(i) treating ketal ester of atorvastatin with aqueous acid in the presence of a lower chain alcohol at 25 to 30° C followed by adding aqueous solution of sodium hydroxide at 10 to 30° C to adjust the pH at 10 to 13 to form atorvastatin sodium; (ii) purifying the atorvastatin sodium by distilling out the lower chain alcohol at 30-50° C and extracting the residue using binary organic solvent mixture followed by isolating the atorvastatin sodium by distilling out the organic solvent mixture from the extract at 35-50° C;
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(iii) crystallizing the atorvastatin sodium with C2-C5 alcohol to obtain crystalline atorvastatin sodium; and
(iv) converting the crystalline atorvastatin sodium to amorphous atorvastatin calcium by treating the crystalline atorvastatin sodium with aqueous solution calcium acetate at 35-55° C in the presence of a mixture of water and water miscible organic solvent; by adding water immiscible organic solvent to the aqueous reaction mixture containing atorvastatin calcium; separating the organic phase from the aqueous phase followed by washing the organic phase with water and distilling out the organic solvent from the organic phase at 40° to 60° C under vacuum to obtain the amorphous atorvastatin calcium.
Preferably, the process of preparing the atorvastatin sodium in step (i) comprising treating the ketal ester of atorvastatin with the aqueous acid selected from perchloric acid, or hydrochloric acid in the presence of lower chain alcohol selected from methanol, ethanol, isopropanol or isobutanol at 25 to 30° C followed by adding aqueous sodium hydroxide at 15 - 25° C and adjusting pH of the reaction mixture to 10.5 to 12.5 to obtain the atorvastatin sodium.
Preferably, the aqueous acid used in step (i) is hydrochloric acid.
Preferably, the binary organic solvent mixture used in step (ii) comprising ethyl acetate and hexane in the ratio of 1:1 v/v.
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Preferably the C2 to C5 alcohol used in step (iii) is selected from ethanol, isopropyl alcohol or isobutanol.
Preferably, the water immiscible organic solvent used in step (iv) is selected from ethyl acetate, tetrahydrofuran, cyclohexane, methylene chloride, diisopropyl ether, pentane, hexane or combinations thereof.
According to another embodiment of the invention the conversion of the crystalline atorvastatin sodium to amorphous atorvastatin calcium as per step (iv) is carried out by treating the crystalline atorvastatin sodium with aqueous solution calcium acetate at 35-55° C in the presence of a mixture of water and water miscible organic solvent; distilling out the solvent from the aqueous reaction mixture at 40 - 45°C under vacuum; dissolving the residue in tetrahydrofuran followed by distilling out the tetrahydrofuran from the solution at 70 to 75° C under vacuum; further dissolving the residue in tetrahydrofuran to obtain clear solution; adding the clear solution to chilled cyclohexane at 15 to 20° C; filtering out the amorphous atorvastatin calcium; washing the product with chilled cyclohexane and drying it under vacuum at 40 to 50° C.
According to yet another embodiment of the invention the conversion of the crystalline atorvastatin sodium to amorphous atorvastatin calcium as per step (iv) is carried out by treating the crystalline atorvastatin sodium with aqueous solution calcium acetate at 35-55° C in the presence of a mixture of water and water miscible organic solvent; distilling out the solvent from the aqueous reaction mixture at 40 - 45°C under vacuum; adding
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mixture of methanol and distilled water to the residue with stirring at 35 to 40° C; adding methylene chloride to the mixture with stirring at 35 to 40° C; separating the organic phase followed by distilling out the solvent partially at 30 to 35° C under vacuum; adding the organic phase to chilled diisopropyl ether at 0 to 5° C; filtering out amorphous atorvastatin calcium; washing it with chilled isopropyl alcohol and drying it under vacuum at 40 to 50° C.
According to yet another embodiment of the invention the conversion of the crystalline atorvastatin sodium to amorphous atorvastatin calcium as per step (iv) is carried out by treating the crystalline atorvastatin sodium with aqueous solution calcium acetate at 35-55° C in the presence of a mixture of water and water miscible organic solvent; distilling out the solvent from the aqueous reaction mixture at 40 to 45°C under vacuum; adding isopropyl alcohol to the residue followed by distilling out the isopropyl alcohol at 50 to 55° C under vacuum; refluxing the residue with isopropyl alcohol and cooling the reaction mixture to 0 to 5° C; filtering out amorphous atorvastatin calcium; washing it with chilled isopropyl alcohol at 5 to 25° C and drying it under the vacuum at 40 to 45°C.
Preferably the water miscible organic solvent used in the conversion of the crystalline atorvastatin sodium to amorphous atorvastatin calcium is selected from methanol, ethanol, isopropyl alcohol or isobutanol.
According to the invention there is also provided amorphous atorvastatin calcium prepared by the above mentioned process.
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The invention provides a process for the preparation of amorphous atorvastatin calcium without formation of mixture of amorphous and crystalline atorvastatin calcium. As the intermediate, atorvastatin sodium, formed in the process is isolated, purified and further crystallized; the final product of the invention is of high purity and good yield. Therefore, it eliminates the extensive and elaborate purification procedures of the final product. It uses inexpensive and easily available solvents and reagents and low temperatures and process steps, which are simple and easy to carry out. The time required to dry the amorphous atorvastatin calcium of the invention is 10 to 30 hours. Thus the drying time for the final product is reduced. Exposure of the product to high temperatures is correspondingly reduced thereby reducing degradation of the product and formation of impurities and improving yield of amorphous atovastatin calcium. For the reasons stated above, the process of the invention is simple and easy to carry out and economical besides being suitable for plant scale manufacture.
The invention is illustrated by the following examples, which should not be construed to be limiting the scope of the invention.
Example 1
Preparation of amorphous atorvastatin calcium by isolating crystalline atorvastatin sodium and without forming crystalline atorvastatin calcium.
20 gm of ketal ester of atorvastatin was charged to methanol (500 ml) at room temperature and stirred at 40-45° C for 1 hour. The reaction mixture was cooled to room temperature. To this, aqueous hydrochloric acid (5.6 ml concentrate hydrochloric acid + 38.4 ml water) was added drop wise with stirring for 8 hours at 25 to 30° C and then
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mixture was cooled to 20°C. Aqueous solution of sodium hydroxide (10 %) was added to the reaction mixture to adjust the pH to 11 by maintaining the temperature at 20°C. The reaction mixture was filtered and washed with 20 ml methanol. Methanol was distilled out from the filtered reaction mixture to obtain residue comprising atorvastatin sodium. The residue was dissolved in water (154 ml) and methanol (144 ml) mixture to get the clear solution. The reaction mixture was extracted 2 times with mixture of ethyl acetate and hexane (62+62 ml). The extract was distilled and degassed under vacuum at 40 - 45° C. lOOmL Isopropropyl alcohol was added to the residue and distilled and degassed under vacuum at 40-45° C. To the degassed mass, 300mL Isopropropyl alcohol was added and was refluxed for 30 min. The reaction mass was then cooled to room temperature in 3 hours and then filtered and dried under vacuum at 50° C for 12 hrs to obtain crystalline atorvastatin sodium.
Yield of crystalline atorvastatin sodium =18 gm. Purity of crystalline atorvastatin sodium = 99%.
15 g of crystalline atorvastatin sodium was dissolved in mixture of methanol (150 ml) and water (50 ml) and the solution was heated to 45°C. To this solution, aqueous solution of calcium acetate (2.02g in 57 ml water) was added in 60 mins under stirring at 45°C and the mixture was maintained at same temperature under stirring for 40 mins. To this solution, 100 ml of ethyl acetate and 100 ml of water were added and the reaction mixture was stirred for 30 mins. The reaction mass was cooled and the ethyl acetate layer was separated. The ethyl acetate layer was washed twice with water (each 50 ml). The ethyl acetate layer was distilled and degassed under vacuum at 50°C to obtain amorphous atorvastatin calcium. The amorphous atorvastatin calcium was dried under vacuum at 50°C for 15 hrs.
Yield of amorphous atorvastatin calcium = 13 gm Purity of amorphous atorvastatin calcium = 99.6 %
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Example 2
Preparation of amorphous atorvastatin calcium by isolating crystalline atorvastatin sodium and without forming crystalline atorvastatin calcium
The amorphous atorvastatin calcium was prepared according to the example 1 using isobutanol for crystallization of atorvastatin sodium instead of isopropyl alcohol.
Yield of crystalline atorvastatin sodium = 18.5 gm. Purity of crystalline atorvastatin sodium = 99%.
Yield of amorphous atorvastatin calcium = 13 g Purity of amorphous atorvastatin sodium = 99.5 %
Example 3
Preparation of amorphous atorvastatin calcium by isolating crystalline atorvastatin sodium and without forming crystalline atorvastatin calcium
Crystalline atorvastatin sodium was prepared according to the Example 1.
15 g of crystalline atorvastatin sodium was dissolved in mixture of methanol (175 ml) and water (50 ml) and the solution was heated to 45°C. To this solution, aqueous solution of calcium acetate (2.02 g in 57 ml water) was added in 60 mins under stirring at 45°C and was maintained under stirring for 30 mins. To this solution, 100 ml of dichloromethane and 100 ml of water were added and the mixture obtained was stirred for 30 mins. The reaction mass was cooled and the dichloromethane layer was separated. The dichloromethane layer was washed twice with water (each 50 ml). The separated dichloromethane layer was distilled and degassed under vacuum at 50°C to obtain amorphous atorvastatin calcium. The amorphous atorvastatin calcium then was dried under vacuum at 50°C for 12 hrs.
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Yield of amorphous atorvastatin calcium = 13 gm Purity of amorphous atorvastatin calcium = 99.55 %
Example 4
Preparation of amorphous atorvastatin calcium by isolating crystalline atorvastatin sodium and without forming crystalline atorvastatin calcium
Crystalline atorvastatin sodium was prepared according to the Example 1.
15 g of crystalline atorvastatin sodium was dissolved in mixture of methanol [175 ml] and water (50 ml) and the solution was heated to 45°C. To this solution, aqueous solution of calcium acetate (2.02g in 57 ml water) was added in 60 mins and the mixture was stirred for 30 mins. The reaction mass was then distilled and degassed under vacuum at 45°C. To the residue, tetrahydrofuran (50 ml) was added and again distilled and degassed at 70 to 75°C under vacuum. The reaction mass was cooled to room temperature and tetrahydrofuran (75 ml) was added till the clear solution obtained. The cyclohexane (375 ml) was cooled to 15°C. Then the reaction mass was added to cooled cyclohexane at 15 °C in 2 hours and maintained the reaction mixture at same temperature for 1 hour. The amorphous atorvastatin calcium was filtered, washed with chilled cyclohexane (15 ml) and dried under vacuum at 50°C for 12 hours.
Yield of amorphous atorvastatin calcium = 13 gm Purity of amorphous atorvastatin calcium = 99.4%
Example 5
Preparation of amorphous atorvastatin calcium by isolating crystalline atorvastatin sodium and without forming atorvastatin calcium
Crystalline atorvastatin sodium was prepared according to the Example 1.
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15 g of crystalline atorvastatin sodium was dissolved in mixture of methanol (150 ml) and water (50 ml) and the solution was heated to 40°C. To this solution, aqueous solution of calcium acetate (2.02g in 57 ml water) was added in 60 mins and the mixture was stirred for 60 mins. The reaction mass was then distilled and degassed under vacuum at 40°C. To the residue, 60 ml methanol and 120 ml distilled water was added and stirred for 30 mins at 35°C. Then methylene chloride (140 ml) was added and stirred for 20 mins at 35°C. The organic layer was separated and aqueous layer was re-extracted with methylene chloride. The organic layer was combined and concentrated to half the volume by distilling out under vacuum at 30 to 35°C. Diisopropylether (250 ml ) was chilled to 0 - 5°C and the concentrated organic layer was added to it at 0 - 5°C in 60 mins. The reaction mixture was maintained at 0 - 5°C for 50 mins. The amorphous atorvastatin calcium obtained was filtered, washed with chilled diisopropylether (15 ml) and dried under vacuum at 50°C for 12 hour.
Yield of amorphous atorvastatin calcium = 13 gm Purity of amorphous atorvastatin calcium = 99.45%
Example 6
Preparation of amorphous atorvastatin calcium by isolating crystalline atorvastatin sodium and without forming crystalline atorvastatin calcium
Crystalline atorvastatin sodium was prepared according to the Example 1.
15 g of crystalline atorvastatin sodium was dissolved in mixture of methanol (175 ml)] and water (70 ml) and the solution was heated to 50°C. To this solution, aqueous solution of calcium acetate (2.02g in 57 ml water) was added in 90 mins and was stirred for 60 mins. The reaction mass was then distilled and degassed at 45°C under vacuum. To the residue, isopropyl alcohol (50 ml) was added and subsequently distilled out the isopropyl alcohol and degassed at 50 to 55° C under vacuum. To this, isopropyl alcohol (175 ml)
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was added and the reaction mass was refluxed for 45 mins. Further the reaction mass was cooled slowly to 0 - 5°C in 4 hrs and the mixture was maintained at 0 - 5°C for 4 hrs. The amorphous atorvastatin calcium obtained was filtered and washed with chilled isopropyl alcohol (25 ml) and dried under vacuum at 45°C for 15 hour.
Yield of amorphous atorvastatin calcium = 12 gm Purity of amorphous atorvastatin calcium = 99.45%
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We claim
1. A process of preparing amorphous atorvastatin calcium comprising the following
steps:
(i) treating ketal ester of atorvastatin with aqueous acid in the presence of a lower chain alcohol at 25 to 30° C followed by adding aqueous solution of sodium hydroxide at 10 to 30° C to adjust the pH at 10 to 13 to form atorvastatin sodium;
(ii) purifying the atorvastatin sodium by distilling out the lower chain alcohol at 30-50° C and extracting the residue using binary organic solvent mixture followed by isolating the atorvastatin sodium by distilling out the organic solvent mixture from the extract at 35-50° C;
(iii) crystallizing the atorvastatin sodium with C2-C5 alcohol to obtain crystalline atorvastatin sodium; and
(iv) converting the crystalline atorvastatin sodium to amorphous atorvastain calcium by treating the crystalline atorvastatin sodium with aqueous solution of calcium acetate at 35-55° C in the presence of a mixture of water and water miscible organic solvent; adding a water immiscible organic solvent to the aqueous reaction mixture containing amorphous atorvastatin calcium; separating the organic phase from the aqueous phase followed by washing the organic phase with water and distilling out the organic solvent from the organic phase at 40 to 60° C under vacuum to obtain the amorphous atorvastatin calcium.
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2. The process as claimed in claim 1, wherein step (i) is carried out by treating the ketal ester of atorvastatin with the aqueous acid selected from perchloric acid or hydrochloric acid in the presence of lower chain alcohol selected from methanol, ethanol, isobutanol or isopropanol at 25 to 30° C followed by adding aqueous sodium hydroxide at 15-20° C and adjusting pH of the reaction mixture to 11 to 13 to obtain the atorvastatin sodium.
3. The process as claimed in claim 1, wherein the binary organic solvent mixture used in step (ii) comprises ethyl acetate and hexane in the ratio of 1:1 v/v.
4. The process as claimed in claim 1, wherein the C2 to C5 alcohol used in step (iii) is selected from ethanol, isopropyl alcohol or isobutanol.
5. The process as claimed in claim 1, wherein the water immiscible organic solvent used in step (iv) is selected from ethyl acetate, tetrahydrofuran, cyclohexane, methylene chloride, hexane, pentane or diisopropyl ether or combinations thereof.
6. The process as claimed in claim 1, wherein the conversion of the crystalline atorvastatin sodium to amorphous atorvastain calcium as per step (iv) is carried
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out by treating the crystalline atorvastatin sodium with aqueous solution of calcium acetate at 35-55° C in the presence of a mixture of water and water miscible organic solvent; distilling out the solvent from the aqueous reaction mixture at 40 - 45°C under vacuum; dissolving the residue in tetrahydrofuran followed by distilling out the tetrahydrofuran from the solution at 70 to 75° C under vacuum; further dissolving the residue in tetrahydrofuran to obtain clear solution; adding the clear solution to chilled cyclohexane at 15 to 20° C; filtering out the amorphous atorvastatin calcium; washing the product with chilled cyclohexane and drying it under vacuum at 40 to 50° C .
7. The process as claimed in claim 1, wherein the conversion of the crystalline atorvastatin sodium to amorphous atorvastain calcium as per step (iv) is carried out by treating the crystalline atorvastatin sodium with aqueous solution of calcium acetate at 35-55° C in the presence of a mixture of water and water miscible organic solvent; distilling out the solvent from the aqueous reaction mixture at 40 - 45°C under vacuum; adding mixture of methanol and distilled water to the residue with stirring at 35 to 40° C; adding methylene chloride to the mixture with stirring at 35 to 40° C; separating the organic phase followed by distilling out the solvent partially at 30 to 35° C under vacuum; adding the organic phase to chilled diisopropyl ether at 0 to 5° C; filtering out amorphous atorvastatin calcium; washing it with chilled isopropyl alcohol and drying it under vacuum at 40 to 50° C.
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8. The process as claimed in claim 1, wherein the conversion of the crystalline atorvastatin sodium to amorphous atorvastatin calcium as per step (iv) is carried out by treating the crystalline atorvastatin sodium with aqueous solution of calcium acetate at 35-55° C in the presence of a mixture of water and water miscible organic solvent; distilling out the solvent from the aqueous reaction mixture at 40 to 45°C under vacuum; adding isopropyl alcohol to the residue followed by distilling out the isopropyl alcohol at 50 to 55° C under vacuum; refluxing the residue with isopropyl alcohol and cooling the reaction mixture to 0 to 5° C; filtering out amorphous atorvastatin calcium; washing it with chilled isopropyl alcohol at 5 to 25° C and drying it under the vacuum at 40 to 45°C.
9. The process as claimed in claim 1, 6, 7 or 8, wherein the water miscible organic solvent used in the conversion of the crystalline atorvastatin sodium to amorphous atorvastatin calcium is selected from methanol, ethanol, isopropyl alcohol or isobutanol.
10. Amorphous atorvastatin calcium prepared by the process as claimed in any of the claims 1 to 9.

Abstract
A simple and economical process for the preparation of amorphous atorvastatin calcium in high purity and good yield from crystalline atorvastatih sodium without forming crystalline atorvastatin calcium is disclosed.