AN IMPROVED PROCESS FOR THE PREPARATION OF AMORPHOUS ATORVASTATIN CALCIUM

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of pure amorphous atorvastatin calcium free of inorganic impurities. BACKGROUND OF THE INVENTION

Atorvastatin calcium is chemically known as [R-(R ^* , R ^* )]-2-(4-fluorophenyl)- 3,5-dihydroxy-5-(1 -methyl ethyl)-3-phenyl- 4 -[(phenyl amino) carbonyl]-1 H-pyrrole- 1 -heptanoic acid, calcium salt having the structural formula-1 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 hyperlipidemia and hypercholesterolemia.

It is known that the amorphous form of atorvastatin calcium exhibits better dissolution characteristics and bioavailability compared to its crystalline forms. Atorvastatin calcium is sparingly soluble in water and it has been found that in comparison to crystalline form, amorphous form of atorvastatin calcium is more suitable for pharmaceutical preparations. US 5,273,995 disclose the hemi calcium salt of atorvastatin. US Patent Nos. 5,003,080; 5,103,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251 ; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,342,952, 5,397,792, WO2006/048888 and WO2005/100313 disclose various processes and key intermediate for preparing atorvastatin calcium. A drawback of the prior arts cited above is that none of these processes consistently produce only amorphous atorvastatin calcium but generally result in a mixture of its crystalline and amorphous forms.

WO 03/093233 describes a process for the preparation of atorvastatin calcium salt in amorphous form comprising: a) dissolving the atorvastatin calcium salt in a water miscible organic solvent, b) gradually adding the said solution to water while stirring, c) filtering and vacuum drying the solid for getting amorphous atorvastatin calcium. This application is silent about the purity of amorphous atorvastatin calcium.

WO2005/005384 describes a process for the preparation of amorphous atorvastatin calcium salt from atorvastatin tert-butyl ester comprising: (a) dissolving atorvastatin tert-butyl ester in an organic solvent, (b) adding an aqueous solution of alkaline or alkaline earth metal hydroxide, (c) removing of the solvent, b) adding water and a water immiscible solvent, e) adding an aqueous solution of calcium salt, f) separating of the phases and removing of the solvent to obtain amorphous atorvastatin calcium and hydrates thereof. This application is silent about the yield and purity of amorphous atorvastatin calcium.

WO02/083638 describes the process for the preparation of atorvastatin calcium in amorphous form comprising: a) treating diol protected tert-butyl ester of atorvastatin in methanol with an aqueous acid; b) adding aqueous hydroxide solution to the reaction mixture; and removing unreacted diol protected tert-butyl ester of atorvastatin by solvent extraction; c) treating the product obtained in step (b) with calcium chloride solution to obtain precipitate of amorphous atorvastatin calcium; d) isolating the said precipitated material followed by drying to get crude amorphous atorvastatin calcium;; e) reacting the crude amorphous atorvastatin calcium with aqueous solution of ethyl acetate followed by treating with activated carbon to get clear solution of atorvastatin calcium in aqueous ethyl acetate; f) recovering the product by addition of non polar hydrocarbon solvent followed by filtration and drying to produce pure amorphous atorvastatin calcium. US 6,528,660 describes a process for the preparation of amorphous atorvastatin calcium and hydrates thereof which comprises: a) dissolving crystalline atorvastatin calcium in a non-hydroxylic solvent; b) adding a non-polar hydrocarbon anti-solvent or adding the dissolved atorvastatin calcium to the non-polar hydrocarbon anti-solvent to precipitate atorvastatin calcium; and c) removing the solvent by filtration to afford amorphous atorvastatin calcium.

WO2006/01 1 155 describes one pot process for the preparation of amorphous atorvastatin calcium comprising: a) contacting (4R-Cis)-1 -1 -dimethylyl 6-[2[2-(4- fluorophenyl)-5-(1 -methylethyl)-3-phenyl-4[(phenylaminocarbonyl]-1 H-pyrral-1 - yl]ethyl]-2,2-dimethyl-1 ,3-dioxane-4-acetate with a water miscible polar organic solvent; b) treating with aqueous mineral acid; c) neutralizing and hydrolyzing using aqueous alkali hydroxide; d) reducing the volume of step (c) to one fourth, adding water, polar organic solvent and methyl-t-butylether and stirring; e) separating the aqueous and organic layer, extracting aqueous layer with a mixture of alkane and alkyl ester solvent: f) adjusting the pH to 7.5 to 8.5 with aqueous hydrochloric acid under stirring, heating at a temperature between 40 °C to 55 °C; g) adding aqueous calcium acetate solution, seeding the turbid solution with amorphous atorvastatin calcium, separating the precipitated solid followed by drying to obtain amorphous atorvastatin calcium.

Most of the above prior art processes for making calcium salt of atorvastatin proceed through preparing a sodium salt intermediate by using combination of water, water miscible organic solvent and aqueous alkali like sodium hydroxide. The sodium salt intermediate is treated with calcium salt, for example calcium acetate to generate atorvastatin calcium. Use of water miscible organic solvent makes it difficult to get rid of inorganic impurities that formed during this step due to solubility of these impurities in reaction mixture containing water and water miscible organic solvents. This leads to atorvastatin calcium contaminated with inorganic impurities.

Amorphous atorvastatin calcium monograph in Indian Pharmacopoeia-(2007) has „methanol solubility%otest wherein atorvastatin calcium containing inorganic impurities fails to pass this test. Further, some of the above processes are highly sensitive and are not consistently reproducible and have unsuitable filtration and drying process for large scale production of atorvastatin calcium.

There is need to provide process for making highly pure amorphous atorvastatin calcium free from inorganic impurities. The improved process of the present invention addresses the need.

OBJECT OF THE INVENTION

The object of the present invention is to provide an improved process for the preparation of amorphous atorvastatin calcium.

Another object of the present invention is to provide an improved process for the preparation of pure amorphous atorvastatin calcium.

Yet another object of the present invention is to provide amorphous atorvastatin calcium free of inorganic impurities.

Yet another object of the present invention is to provide industrially scalable and reproducible process for the preparation of amorphous atorvastatin calcium.

DESCRIPTION OF THE DRAWINGS:

Figure 1 X-Ray diffractogram of amorphous form of atorvastatin calcium.

Figure 2 Purity of the amorphous atorvastatin calcium by HPLC

DETAILED DESCRIPTION OF THE INVENTION

The process of the present invention is depicted in following scheme:

Formula 1

In accordance with the above scheme, pure amorphous atorvastatin calcium is prepared by the process comprising steps: A. reacting (3R,5R)-2-(4-fluorophenyl)-3,5-dihydroxy-5-(1 -methylethyl)-3-phenyl- 4-[(phenyl amino) carbonyl]-1 H-pyrrole-1 -heptanoic acid t-butyl ester (formula- 2) with aqueous alkali in water immiscible organic solvent;

B. diluting the reaction mixture with water immiscible organic solvent followed by reacting with a calcium ion source;

C. separating layers and extracting the aqueous layer with water immiscible organic solvent;

D. washing and filtering the organic layer followed by recovery of organic solvent to obtain an oily residue;

E. dissolving the oily residue in ethyl acetate while maintaining the moisture level below 1 .0%;

F. adding the reaction mixture of step-(E) in non-polar organic solvent followed by isolating the precipitate and drying to yield pure amorphous atorvastatin calcium.

Step - A of the reaction comprises reacting a compound of formula 2 with aqueous alkali in water immiscible organic solvent at 25-50 °C, preferably at 45-45 °C to obtain an alkali metal salt of atrovastatin. On completion of the reaction, a water immiscible organic solvent is added to the reaction mixture followed by reacting with a calcium ion source to obtain arotvastatin calcium.

The alkali is selected from alkali metal hydroxides such as 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 preferable alkali is sodium hydroxide.

The Water immiscible organic solvent is selected from 2-methyl tetrahydrofuran, diethyl ether, methyl tertiary butyl ether, diisopropyl ether or mixtures thereof. The preferable water immiscible organic solvent is 2-methyl tetrahydrofuran.

The calcium ion source is selected from calcium chloride, calcium acetate, calcium gluconate and like. The preferable calcium ion source is calcium acetate.

The non-polar organic solvent is selected from cyclohexane, hexanes, heptanes, methyl t-butyl ether, diisopopropyl ether or mixtures thereof. The preferable non-polar organic solvent is hexane or heptane, more preferably is heptane. The non-polar organic solvent is optionally charged in another reactor fitted with inert gas such as argon, nitrogen and likes to avoid the formation of oxidative impurities.

The moisture level of the reaction mixture is maintained below 1 .0% in step - E by appropriately removing ethyl acetate. Preferably, the moisture level of reaction mixture is maintained below 0.5%.

In accordance with the preferred embodiment the wet atorvastatin calcium obtained in step - F is dried at 28-32 °C for 12-24 hrs followed by micronization and further dried at 35-50 °C to obtain pure amorphous atorvastatin calcium. The product obtained from the above process has HPLC purity ^Q 99.5% and the total impurity less than 0.2%. The end product is free of inorganic impurities.

The process for the preparation of pure amorphous atorvastatin calcium is explained by the following non-limiting examples:

Example 1 : Preparation of amorphous atorvastatin calcium (formula-1 ):

(3R,5R)2-(4-fluorophenyl)-3,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-

[(phenylamino) carbonyl]-IH-pyrrole-l-heptanoic acid t-butyl ester (100 gm) was stirred in 2-Methyl THF (200 ml) at 40- 45°C and reacted with a solution of sodium hydroxide (8 gm) in water (200 ml). The reaction mixture was diluted by 2-methyl THF (800 ml) followed by adding a solution of calcium acetate (16.3 gm) in water. After separating the layer, the aqueous layer was extracted with 2-Methyl THF and the organic layer was washed with water followed by filtration to remove undissolved solids and recovery of 2-Methyl THF. The oily residue of atorvastatin calcium formed was dissolved in ethyl acetate (1000 ml) while maintaining the moisture level below 1 .0%. The solution was treated with heptane and filtered. The precipitate formed was dried at 30°C up to 20 hrs followed by micronization. The micronized precipitate was again dried at 40°C to yield pure amorphous atorvastatin calcium.

(Yield = 86.00 gm, HPLC Purity = 99.85 %)

Example 2: Preparation of amorphous atorvastatin calcium (formula-1 ):

(3R,5R)2-(4-fluorophenyl)-3,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-

[(phenylamino) carbonyl]-IH-pyrrole-l-heptanoic acid t-butyl ester (100 gm) was stirred in 2-Methyl THF (200 ml) at 40- 45°C and reacted with a solution of sodium hydroxide (8 gm) in water (200 ml). The reaction mixture was diluted by 2-methyl THF (800 ml) followed by adding a solution of calcium acetate (16.3 gm) in water. After separating the layers, the aqueous layer was extracted with 2-Methyl THF and the organic layer was washed with water followed by filtration to remove undissolved solids and recovery of 2-Methyl THF. The oily residue of atorvastatin calcium formed was dissolved in ethyl acetate (1000 ml) while maintaining the moisture level below 1 .0%. The solution was treated with heptane and filtered. The precipitate formed was dried at 30°C up to 20 hrs followed by micronization. The micronized precipitate was again dried at 40°C to yield pure amorphous atorvastatin calcium.

(Yield = 86.4 gm, HPLC Purity = 99.84 %)

Example 3: Preparation of amorphous atorvastatin calcium (formula-1 ):

(3R,5R)2-(4-fluorophenyl)-3,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4- [(phenylamino) carbonyl]-IH-pyrrole-l-heptanoic acid t-butyl ester (100 gm) was stirred in 2-Methyl THF (200 ml) at 40- 45°C and reacted with a solution of sodium hydroxide (8 gm) in water (200 ml). The reaction mixture was diluted by 2-methyl THF (800 ml) followed by adding a solution of calcium acetate (16.3 gm) in water. After separating the layers, the aqueous layer was extracted with 2-Methyl THF and the organic layer was washed with water followed by filtration to remove undissolved solids and recovery of 2-Methyl THF. The oily residue of atorvastatin calcium formed was dissolved in ethyl acetate (1000 ml) while maintaining the moisture level below 1 .0%. The solution was treated with heptane and filtered. The precipitate formed was dried at 30°C up to 20 hrs followed by micronization. The micronized precipitate was again dried at 40°C to yield pure amorphous atorvastatin calcium. (Yield = 88.00 gm, HPLC Purity = 99.82 %)