FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
AN IMPROVED PROCESS FOR THE PREPARATION OF AMORPHOUS
ATORVASTATIN CALCIUM
2. APPLICANT(S)
(a) NAME : CADILA PHARMACEUTICALS LTD.
(b) NATIONALITY : An INDIAN Company
(cj ADDRESS : "Cadila Corporate Campus", Sarkhej'-Dholka Road, Bhat, Ahmedabad - 382210.Gujarat, India,
3. PREAMBLE TO THE DESCRITION
PROVISIONAL
The following specification describes invention
4. DESCRIPTION (Description shall start from next page)

FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of Atorvastatin calcium in amorphous form. Tine invention also reates to an improved process for the preparation of amorphous atorvastatin calcium comprising: reaction of (βR,ỡR)-2-(4-fuorophenyl)-β-ỡ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenyI 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 which is then converted to Atorvastatin calcium by treating with calcium source.
BECKGROUND OF THE INVENTION
Atorvastatin calcium is chemically known as [R-(R*. R*)]-2-(4-fluorophenyl)-B,ỡ-dihydroxy-5-(1-methyl ethyl)-3-phenyl- 4 -[(phenyl amino) carbonyl]-1 H-pyrrole-1-heptanoic acid, calcium salt (2:1) having the structural formula (I) as follows.

Atorvastatin is therapeutically useful as an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and is used for the treatment of hyperlipidemi and hypercholesterolemis
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 {Formula 3) 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 to provide atorvastatin calcium,
(c) isolation of atorvastatin calcium from reaction mixture 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, butyl 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 the 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 reduced levels of related substances with better purity.
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: reaction of (PR,5R)-2-(4-fuorophenyi)-β,ỡ,-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 meta! salt of atorvastatin which is then converted to Atorvastatin calcium by treating with calcium source.
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, alkafine 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: journal of The American Institute of Chemical Engineers (AlChE) 1992 vol 38 no. 3 pages 397-404).
Most of the prior art processes make use of combination of water and 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 contaminate 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-precipitate and contaminate 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.


In accordance with the present invention, amorphous Atorvastatin calcium is prepared by a process comprising steps:
a) reacting (βR,ỡR)-2-(4-fuorphenyl)-β,ỡ-dihydroxy-5-(1methylethyl)-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 (in situ)
b) diluting reaction mixture obtained in (a) with water immiscible organic solvent and reaction with calcium ion source.
c) washing the organic layer with water, and filtering organic layer through micro filter to remove un-dissolved matter; removing organic solvent under vacuum,
d) adding water miscible organic solvent and stirred,
e) adding non-polar organic solvent in another reactor fitted with Nitrogen followed by adding reaction mixture with water miscible organic solvent to reactor with previously heated non-polar organic solvent and stirred. The reaction mixture is cooled at temperature 25-30°C with stirring.
f) filtering the product followed by washing with non-polar organic solvent,
g) isolating and drying the material under vacuum to give amorphous Atorvastatin Ca.
In step-(a), the base used, is selected from group comprising 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 or 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 2-methyl tetrahydro 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 solvent: water) It is one of the embodiment of present invention.
In step-(b) alkali metal salt of atorvastatin, obtained in situ through saponification step is diluted with water immiscible organic solvent and treated with calcium source 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.
Upon the completion of reaction, the layers are separated. Aqueous layer is extracted with organic water immiscible solvent, and the layers are separated and organic layers are combined.
In step-(c), organic layer is washed with water and organic layer is filtered through micro filter to remove un-dissolved matter. The organic solvent is removed under vacuum.
In step-(d) water miscible organic solvent is charged again and stirred.
In step-(e) non-polar organic solvent is charged in another reactor fitted with Nitrogen system. The non-polar organic solvent is selected from cyclohexane, hexane, heptane, methyl t-butyl ether, diispopropyl ether or mixtures thereof. The heptane is preferred according to present invention. The reaction mixture with miscible organic solvent is added the previously heated reactor of non-polar organic solvent and stirred, cooled and again stirred at temperature 25-300C.
In step (f) the product is filtered and slurry is washed with non-polar organic solvent. The product is isolated and dried under vacuum to give amorphous Atorvastatin Ca.
The invention is now illustrated with some non-limiting example. Example-1: Preparation of amorphous Atorvastatin calcium (formula-l):
200 ml of water is charged in the reactor fitted with Nitrogen. 8 gm of Sodium Hydroxide is charged & stir till get dissolved. 200 ml of 2-Methyl Tetrahydro furan is added and stirred. The reaction mixture is heated till about 40- 45°C. 100 gm of (PR,5R)2-(4-

fuorophenyl)-β,ỡ-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino) carbonylj-IH-Pyrrole-l-heptanoic acid t-butyl ester (formula III) is charged and reaction mass is stirred. 800 ml of 2-Methyl THF is charged into the reaction mass and stirred.
The solution of 16.3 gm Calcium acetate in water is added and stirred. Organic layers are settled and separated. The aqueous layer is extracted with 500ml of 2-Methyl THF at 40 - 45°C. Both organic layers are combined and the organic layer is washed thrice purified water. The organic layer is filtered through micro filter to remove un-dissolved matter.
2-methyl THF is removed under vacuum and Nitrogen is released. Freshly distilled 1L of Ethyl acetate is charged and stirred. The material is dissolved and ethyl acetate is recovered completely under vacuum. Freshly distilled 1250 ml of Ethyl acetate is charged and stir at 40-45°C to dissolve the product. 2500 ml of n-Heptane is charged in another reactor fitted with Nitrogen supply and heated upto temp 40-45°C. The reaction mixture is added to previously heated n- heptane reactor and stirred, cooled. The reaction mixture is again stirred at temperature 25-30°C. The product is filtered and dry under nitrogen. Slurry is washed with n-Heptane. The material is dried under vacuum to give amorphous Atorvastatin calcium. (Purity 99.85%)