FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
PROVISIONAL / COMPLETE SPECIFICATION (See section 10 and rule 13)
1. TITLE OF THE INVENTION
AN IMPROVED PROCESS FOR AMORPHOUS ATORVASTATIN CALCIUM
2. APPLICANT(S)
(a) NAME : CADILA PHARMACEUTICALS LTD.
(b) NATIONALITY : An INDIAN Company
(c) ADDRESS : "Cadila Corporate Campus", Sarkhej-Dholka Road, Bhat,
Ahmedabad - 382210.Gujarat, India,

3. PREAMBLE TO THE DESCRITION
PROVISIONAL
The following specification describes invention
COMPLETE
The following specification particularly describes the invention and the manner in which it is to be
4. DESCRIPTION {Description shall start from next page)

FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of amorphous atorvastatin calcium.
BECKGROUND OF THE INVENTION
Atorvastatin calcium is chemically known as [R~(R*, R*)]-2-(4-fluorophenyl)-p,6-dihydroxy-5-(1-methyl ethyl)-3-phenyl- 4 -[(phenyl amino) carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) having the structural formula (I) as follows.

Formula -I
Atorvastatin is therapeutically useful as an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and is used for the treatment of hyperlipidemia and hypercholesterolemia.
It is known that the amorphous form of Atorvastatin calcium exhibits different dissolution characteristics and bioavailability patterns compared to its crystalline forms. Atorvastatin calcium is slightly water-soluble, and it has been

found that in comparison to crystalline form, amorphous form of Atorvastatin calcium is more suitable for pharmaceutical preparations.
US5273995, US5003080; US5103045; US5103024; US5124482; US5149837; US5155251; US5216174; US5245047; US5248793; US5280126; US5342952; US5397792; WO02/057228; WO02/083637; WO02/083638; US6528660(WO00/71116); US6613916; WO01/042209; US6891047; US646133(WOO1/028999); WO03/093233; WO03/099785; US6750353; (WO02/059087); WO2004/085391; WO2004/089895; WO2005/005384; US2005/0032880; (WO2004/110407); US2005/0119493(WO2003/018547); US2005/0131055; (WO03/068739); US2005/0165242; WO2005/073187; WO2005/092852; WO2005/100313; US2005/0261360; US2005/0261359; US2005/0267198; WO2006/011155; WO2006/021969; WO2006/039441; WO2006/046109; WO2006/048888; US2006/0106230(WO2006/045018); US2006/0128971; US6087511(WO97/03960); US6274740, WO2009007856 , WO2008053312 , WO2002057228 , WO07088553 and Journal of Labeled Compounds and Radiopharmaceuticals Vol. 43 pages 261-270 (2000) as per Ex-13 describe processes for preparing atorvastatin calcium.
The general synthetic scheme (scheme-1) followed in prior art starting with atorvastatin tertiary butyl ester (II) is depicted below: Scheme-1


The steps involved are,
(a) Saponification of atorvastatin tertiary butyl ester (II) using aqueous alkali
preferably sodium hydroxide, in the presence of one or more organic
solvents,
(b) Reacting aqueous solution of atorvastatin sodium obtained in (a) with calcium ion source compound to provide atorvastatin calcium,
(c) Isolation of atorvastatin calcium from reaction mixture (b) by precipitation using anti-solvent followed by filtration and drying.
One of the organic solvent used in the saponification step is water miscible organic solvent.
Use of water miscible organic solvent in the saponification step makes it difficult to get rid of inorganic impurities like calcium hydroxide and sodium acetate that formed during the process due to solubility of these compounds in reaction mixture containing water and water miscible organic solvent. This leads to Atorvastatin calcium contaminated with inorganic impurities. Amorphous Atorvastatin calcium monograph in Indian Pharmacopoeia has "methanol solubility" test Atorvastatin calcium containing inorganic impurities fails to pass this test. There is need to provide process for making amorphous Atotvastatin calcium free from inorganic impurities .The improved process of this instant invention addresses this need.
SUMMARY OF THE INVENTION
The object of the present invention is to provide an improved and industrially scalable process for the preparation of amorphous atorvastatin calcium free from inorganic impurities.
Another object of the invention is to provide amorphous atorvastatin calcium having better purity with reduced levels of related substances.

Yet another object of the invention is to provide amorphous atorvastatin calcium soluble in methanol.
Yet another object of the invention is to provide an improved process for the preparation of amorphous atorvastatin calcium comprising,
a) Reacting (pR,6R)-2-(4-fuorophenyl)-P,6-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenyl amino) carbonyl-1H-Pyrrole-1-heptanoic acid t-butyl ester (formula II) in an organic water immiscible solvent, with aqueous alkali to give an alkali metal salt of atorvastatin
b) diluting reaction mixture in step-(a) with water immiscible organic solvent and reacting reaction mixture with calcium source followed by treatment with aqueous acid, followed by washing the organic layer with water,
c) Treating the organic fayer with inorganic salt foffowed by filtration,
d) Optionally concentrating organic layer and treating with anti-solvent to provide amorphous Atorvastatin calcium,
f) Isolation of amorphous Atorvastatin calcium by filtration followed by drying.
DETAILED DESCRIPTION OF THE INVENTION
Base catalyzed hydrolysis of esters of acids to produce salt of acid and alcohol is well known chemical transformation widely used in chemical industry, also referred to as saponification of esters.
The bases commonly used are alkali earth metal hydroxides, alkaline earth metal hydroxides, organic bases like amines, alkoxides etc. (Ref. organic synthesis collective volume 10 page 432; organic synthesis collective volume 9 page 275).
The hydrolysis reactions are usually carried out in homogeneous medium. Heterogeneous reactions under Phase Transfer Conditions are also reported. (Ref: The American Institute of Chemical Engineers [AlChE] journal 1992 vol 38 no. 3 pages 397-404).

Most of the prior art processes make use of combination of water miscible organic solvent .water immiscible organic solvent along with water and inorganic base like sodium hydroxide in this step. The sodium salt of acid obtained is treated with calcium salt for example calcium acetate to generate Atorvastatin calcium. During this step sodium acetate and calcium hydroxide, herein after referred to as "salts" are generated as side products which contaminated with Atorvastatin calcium if not removed during successive processing steps. Removal of salts from reaction mixture containing water and water miscible organic solvent as used in the prior art processes is very difficult due to partial solubility of these salts in mixture of water and water miscible organic solvent. At the time of precipitation of Atorvastatin calcium using anti solvent the salts get co-precipitated and contaminated with Atorvastatin calcium. Indian Pharmacopoeia has "methanol solubility" test incorporated in the Atorvastatin calcium monograph . Samples of Atorvastatin calcium contaminated with trace levels of salt impurities invariably fail to pass this test.
During the investigation of this problem in our laboratory we surprisingly found that the saponification step can be carried out in mixture of water, base and water immiscible organic solvent. The use of water immiscible organic solvent proves beneficial in the successive processing steps wherein salts can be removed by water washing of the organic layer. In the prior art processes due to use of water miscible organic solvent in the saponification step water washing of organic layer is inefficient due to improper layer separation. Consequently trace levels of salts remain in the reaction mixture along with Atorvastatin calcium.

The process of the instant invention is depicted in scheme -2. Scheme-2

2
isolation:
[1] extraction , treatment with antisolvent < [2] filtration , drying
AMORPHOUS ATORVASTATIN CALCIUM
In accordance with the present invention, amorphous Atorvastatin calcium is prepared by a process comprising steps:
a) reacting (pR,6R)-2-(4-fuorophenyl)-p,6-dihydroxy-5-(1 -methylethyl)-3-phenyl-4-[(phenyl amino) carbonyl-1H-Pyrrole-1-heptanoic acid t-butyl ester (formula II) in an organic water immiscible solvent, with aqueous alkali to give an alkali metal salt of atorvastatin
b) Diluting reaction mixture obtained in (a) with water immiscible organic solvent and reaction with calcium ion source compound followed by treatment with aqueous acid.
c) Washing the organic layer with water,
d) Treating the organic layer with inorganic salt followed by filtration,
e) Optionally concentrating organic layer and treating with anti-solvent to provide amorphous Atorvastatin calcium,
f) Isolating amorphous Atorvastatin calcium by filtration followed by drying.

In step-(a), The base used is selected from group comprising of alkali metal
hydroxides like sodium hydroxide, potassium hydroxide, lithium hydroxide,
cesium hydroxide; alkali metal carbonates such as sodium carbonate, potassium
carbonate, lithium carbonate, cesium carbonate and mixtures thereof.
The reaction is generally carried out at room temperature to about 100 °C .
Water immiscible solvent used in the reaction is selected from group comprising
of 2-methyl tetra hydro furan, diethyl ether, methyl tertiary butyl ether, diisopropyl
ether and mixtures thereof.
We surprisingly found that the rate of saponification reaction depends upon the
ratio of quantity of organic solvent and quantity of water used in the reaction. It is
observed that if optimum ratio is maintained reaction can be completed in shorter
time with minimum amount of impurities. The optimum ratio ranges from of 1:20
(organic solvent: water) to 20:1 (organic sofvent: water) At is one of the
embodiment of present invention.
In step-(b) alkali metal salt of atorvastatin , obtained in saponification step is
diluted with water immiscible organic solvent and treated with calcium source
compound to give atorvastatin calcium. The reaction in this step is carried out at
25°C to 80° C.
The calcium source compound is selected from group comprising calcium
chloride, calcium acetate, and calcium gluconate.
After the reaction is over, the layers are separated, aqueous layer is extracted
with organic water immiscible solvent, and the layers are combined. The organic
layer containing atorvastatin calcium is washed with dilute aqueous acid;
aqueous acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid,
nitric acid or C1-C4 organic acids and mixtures thereof.
In step-(c), organic layer is treated with water soluble inorganic salt , selected
from compounds such as sodium sulphate, sodium phosphate, sodium chloride
potassium chloride, potassium sulfate, potassium phosphate and mixtures
thereof followed by filtration.
In step-(d) the solution of atorvastatin calcium obtained may be concentrated,
mixed with water and treated with anti-solvent to precipitate atorvastatin calcium.

The anti-solvent is selected from group comprising cyclohexane, hexane, heptane, methyl t-butyl ether, diispopropyl ether and mixtures thereof. In step-(e) the precipitated amorphous atorvastatin calcium is filtered and dried. Filtration can be done using conventional techniques like vacuum filtration, centnfugation and the like. Care should be taken to avoid exposure of Atorvastatin calcium to atmosphere during filtration and drying operations. Preferably the operations are carried out under inert gas atmosphere of nitrogen, argon etc.
The invention is now illustrated with some non-limiting examples.
Example-1
Preparation of amorphous Atorvastatin calcium (formuia-i):
(PR,6R)2-(4-fuorophenyl)-3,5-dihydroxy-5-(l-methyl^thyl)-3-phenyl-4-[(phenylamino) carbonylj-IH-Pyrrole-l-heptanoic acid t-butyl ester (formula II) (50 gm) was dissolved in 2-methyl THF (50 gm). 1N Sodium hydroxide solution was added with stirring and the reaction mass was stirred for 10 hr at 70°C. After the completion of the reaction, calcium acetate solution (7.73 gm/600 ml water) was added with stirring, the reaction mass was stirred for one hour at 25-30°C. 2-Methyltetrahydrofurane [2-Methyl THF] (600ml) was added and stirred for 15 minutes. The layers were separated. The aqueous layer was extracted with 2-Methyltetrahydrofurane (450ml) and stirred for 10 minutes. The combined organic layers were treated with hydrochloric acid solution (0.10N, 100 ml), The organic layer was treated with sodium chloride (30 gm), layers separated. Aqueous layer was discarded. The organic layer was filtered and the filtrate was then concentrated mixed with 5 ml of water and added to n-hexane: MTBE (200ml: 400ml). The precipitated material was stirred at room temperature (25-30°C), filtered and dried to give amorphous Atorvastatin calcium. Wt. = 35gm