WO2011089559A1

WO2011089559A1 - A novel polymorphic form of atorvastatin salts

Info

Publication number: WO2011089559A1
Application number: PCT/IB2011/050253
Authority: WO
Inventors: Buchi Reddy Reguri; Misra Dharmendra; Peter Paul Raj Medabalimi; Ganesan Subramaniam
Original assignee: Orchid Chemicals And Pharmaceuticals Limited
Priority date: 2010-01-22
Filing date: 2011-01-20
Publication date: 2011-07-28

Abstract

The present invention provides an improved process for the preparation of Atorvastatin of formula (I) or its salts, preferably hemicalcium salt with purity greater than 99.5% using novel salts of Atorvastatin such as N,N- dicyclohexylethylenediamine salt of Atorvastatin and novel polymorph of Atorvastatin sodium salt. Formula (I).

Description

A NOVEL POLYMORPHIC FORM OF ATORVASTATIN SALTS

Field of the Invention The present invention provides an improved process for the preparation of

Atorvastatin of formula (I) or its salts, preferably hemicalcium salt with purity greater than 99.5% using novel salts of Atorvastatin such as N,N- dicyclohexylethylenediamine salt of Atorvastatin and novel polymorph of Atorvastatin sodium salt.

The invention also provides a process for preparatin said salts with increased purity and good yield. The novel salt according to the present invention are useful in the preparation of Atorvastatin calcium.

Background of the Invention Atorvastatin hemicalcium is a synthetic lipid-lowering agent. It is a 3- hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate- limiting step in cholesterol biosynthesis. Inhibition of the enzyme decreases de novo cholesterol synthesis, increasing expression of low-density lipoprotein receptors (LDL receptors) on hepatocytes. This increases LDL uptake by the hepatocytes, decreasing the amount of LDL-cholesterol in the blood. Like other statins, Atorvastatin also reduces blood levels of triglycerides and slightly increases levels of HDL-cholesterol. The chemical designation for Atorvastatin hemicalcium is [R- (R*, R*)]-2-(4-fluorophenyl)- , δ -dihydroxy-5- (l-methylethyl)-3-phenyl-4- [(phenylamino) carbonyl]-lH-pyrrole-l-heptanoic acid, calcium salt (2: 1) trihydrate. This is marketed under the brand name of LIPITOR^®

US patent No. 5,273,995 discloses the mono-sodium, mono-potassium, hemi-calcium, ammonium and N-methylglucamine salts of atorvastatin and also discloses the preparation of atorvastatin hemicalcium salt from atorvastatin sodium. This patent isolates Atorvastatin hemicalcium by dissolving hemi calcium in ethyl acetate followed by addition of hexane to yield amorphous form of Atorvastatin calcium.

WO 97/003958 discloses the teaching of amorphous atorvastatin which has unsuitable filtration and drying for large scale production and discloses that the said amorphous form must be protected from heat, light, oxygen and moisture.

US patent No. 6,838,566 discloses various amine salts of statin derivatives including Atrovastatin, for the preparation of medicament using the said amine salt. Though this patent covers various organic amines, this patent does not provide preparation method of all the amine salts except TBA and DCHA. This patent does not disclose the purity and stability of diamines salts. US patent No. 7,615,647 discloses the various amines salt of atorvastatin and its also teaches the preparation of atorvastatin calcium salt from atorvastatin amine salt. However the purity of amine salt and the hemicalcium slat obtained from the said amine salt is less than 99.5%. Other than the Atorvastatin ammonium salt the organic amine salt of Atorvastatin prepared according to the present invention has purity in the range of 94- 96%.

US patent No. 7,534,810 discloses various atorvastatin amine salt and new crystalline form of atorvastatin sodium salt in view of preparing pharmaceutical composition using these salts.

GB2424880 discloses atorvastatin sodium form I and form II. WO2007118873 discloses atorvastatin sodium of form I, II, III, IV V and amorphous form, the said forms are used for preparing pharmaceutical composition. WO2008053495 (1143/KOL/2006) discloses the preparation of novel crystalline form of atorvastatin sodium. These publication no where provide enablement for the preparation of Atorvastatin calcium using these sodium salt disclosed in the specification. US20070066679 discloses crystalline atorvastatin sodium of form I by treating of amorphous atorvastatin sodium with 85% ethanol solution and acetone.

US20070066678 discloses crystalline atorvastatin sodium of form II by treating of amorphous atorvastatin sodium with 85% ethanol solution and butanone.

The above said literature provides the Atorvastatin sodium or amine salt for the preparation of pharmaceutical composition. There are number of literatures provides a process for the preparation of amorphous Atorvastatin, but said preparation are fails to produce the amorphous form of Atorvastatin having purity greater than 99.5%. And number of literature utilizes the isolation of Atorvastatin in crystalline hemicalcium salt and converts said form into amorphous to achieve the purity.

Considering the commercial importance of Atorvastatin calcium, particularly in the amorphous form, there exists a constant need for developing a process for Atorvastatin in pure form. Applicant surprisingly found that the isolation of Atorvastatin as Ν,Ν-dicyclohexylethylenediamine greatly enhances the purity of Atorvastatin.

Objectives of the Invention

The primary objective of the present invention is to provide the process for preparing Atorvastatin hemicalcium having good purity, greater than 99.5% and stability.

Another objective of the present invention is to provide novel polymorph of Atorvastatin sodium with good stability, purity and yield.

Yet another objective of the invention is to provide Atorvastatin N'N'- dicyclohexylethylenediamine salt with good stability, purity and yield. Summary of the Invention

Accordingly, a first aspect of the present invention directed to an improved process for the preparation of Atorvastatin hemicalcium salt having purity greater than 99.5% which comprising the steps of:

i) hydrolyzing atorvastatin ester of formula (III) using aqueous sodium hydroxide solution in an alcoholic solvent;

(III)

concentrating the step (i) solution;

isolating the Atorvastatin as Ν,Ν-dicyclohexylethylenediamine or as a sodium salt having the PXRD pattern as described in Fig-1; and

converting salt of step (iii) into Atorvastatin of formula (I) or its hemicalcium salt.

(I)

In a second aspect of the inventions directed to novel N,N- dicyclohexylethylenediamine salt of Atorvastatin.

In a third aspect, the present invention directed to novel polymorph of Atorvastatin sodium salt having substantially the same X-ray diffractogram as set out in FIG. 1.

In a fourth aspect of the inventions directed to crystalline form of Ν,Ν-dicyclohexylethylenediamine salt of Atorvastatin having substantially the same X-ray diffractogram as set out in FIG. 2.

In a fifth aspect, the present invention directed to a process for preparing crystalline form of Ν,Ν-dicyclohexylethylenediamine salt of Atorvastatin which comprising the steps of:

i) obtaining solution of Atorvastatin in an organic solvent;

ii) treating the step (i) solution with N,N-dicyclohexylethylenediamine or its salt; and

iii) isolating Atorvastatin N,N-dicyclohexylethylenediamine salt.

Brief description of drawings Fig. 1 shows X-ray powder diffraction pattern of crystalline form of atorvastatin sodium according to the present invention.

Fig. 2 shows X-ray powder diffraction pattern of atorvastatin N'N'-dicyclohexyl ethylenediamine salt according to the present invention. Fig 3 shows amorphous Atorvastatin hemicalcium obtained as intermediate in Method A of Example 3. Fig 4 shows final amorphous Atorvastatin hemicalcium obtained from the present invention.

The PXRD of said salt analyzed using following condition:

Detailed Description of the Invention

In an embodiment of the present invention provides process for the preparation of Atorvastatin hemicalcium from atorvastatin ester of formula (III), particularly tert-buty ester, having purity greater than 99.5% by HPLC. The purity of Atorvastatin hemicalcium is achieved by way isolating the Atorvastatin as N, N- dicyclohexylethylenediamine salt of Atorvastatin or as crystalline sodium salt Atorvastatin having PXRD similar to Fig- 1. The purity of amorphous Atorvastatin calcium as reported in the prior art is less than 99.5%, though some of them involve isolation of amine salt, the Atorvastatin hemicalcium obtained from the said amine is less than 99.5%, hence the selection of amine plays vital role in isolation of Atorvastatin having purity greater than 99.5%. Atorvastatin ester of formula (III) includes lower alky ester, for example tert-butyl ester.

In an embodiment of the present invention, N, N- dicyclohexylethylenediamine salt of Atorvastatin can be isolated either as an amorphous form or in crystalline form. Applicant surprisingly found the isolated Ν,Ν-dicyclohexylethylenediamine salt has high storage stability and purity greater than 99.5%, particularly 99.6%, more particularly >99.7%. In addition the said salt is easy to handle in industrial scale and easy to filter. It should be noted that all amine salt of Atorvastatin does not have said property, some of them are difficult to isolate because of pasty nature, some of them does not have storage stability and some of them are difficult to filter. None of the literature per se discloses the N,N- dicyclohexylethylenediamine salt of Atorvastatin and constitute one of the novelty of the present invention.

The identification of suitable amine salts requires through investigation of many factors, including but not limited to (i) stability & purity of the amine salt (ii) yield and quality of atorvastatin that are prepared from these amine salt {with certain amine the quality of amine salt of Atorvastatin salt is either inferior or the amine salt of atorvastatin is less stable owing to the basicity of amines} (iii) preparation of atorvastatin from the atorvastatin amine salt for example certain amine require strong acid for cleavage of the salt, which affects the quality of final API (iv) cost involved in the manufacturing. Applicant points out the manufacturing cost associated with the preparation of Ν,Ν'-dicyclohexylethylenediamine salt is much less. The reported amine salt fails to produce the Atorvastatin with purity greater than 99.5%. Surprisingly the isolation of Atorvastatin as Ν,Ν'- dicyclohexylethylenediamine salt produce the Atorvastatin with purity greater than 99.5% and the manufacturing cost according to the present invention is less and gives economical advantage to the present process.

In another embodiment of the present invention, crystalline N,N- dicyclohexylethylenediamme salt of Atorvastatin is characterized by having a powder X-ray diffraction pattern with peaks at 6.4, 7.7, 9.3, 10.3, 11.0, 12.7, 15.6, 16.0, 16.9, 17.6, 18.7, 19.2, 19.3, 19.8, 20.1, 20.7, 21.0, 22.0, 22.6, 23.0, 23.4, 23.8, 24.5, 24.8, 25.6, 26.0, 26.3, 26.7, 27.1, 27.8, 28.2, 28.5 and 29.3. ± 0.2 degrees 2Θ. In another embodiment of the present invention, crystalline sodium salt of

Atorvastatin is characterized by having a powder X-ray diffraction pattern with peaks at 4.53, 5.53, 5.99, 8.19, 8.64, 9.59, 10.28, 10.62, 11.09, 12.00, 13.08, 13.66, 14.12, 15.26, 16.34, 16.73, 17.38, 17.58, 18.10, 18.54, 19.30, 19.56, 19.94, 20.76, 21.45, 21.92, 22.35, 23.27, 23.62 23.95, 24.45, 24.77, 25.22, 26.54, 26.86, 27.78, 28.07, 28.96, 29.52, 30.03 and 30.70. ± 0.2 degrees 2Θ.

In still another embodiment of the present invention the solvent used in step (i) in the preparation of N, N dicyclohexylethylenediamme salt is selected from ethyl acetate, isopropylacetate, dichloromethane, toluene and mixture thereof.

In yet another embodiment of the present invention, the hydrolysis of atorvastatin ester of formula (III) is performed in conventional manner using an alcoholic solvent system such as methanol, ethanol, isopropanol and the like or mixture thereof , and the percentage of aqueous sodium hydroxide used in step (i) is in the range of 20-80%; preferably in the range of 40-60%. After hydrolysis the solvent is removed by distillation, preferably by vacuum distillation, from residue atorvastatin is isolated as Ν,Ν-dicyclohexylethylenediamine salt or as sodium salt having PXRD pattern as shown in the Fig-1. Accordingly the isolation Atorvastatin Ν,Ν-dicyclohexylethylenediamine salt is done by adjusting the reaction mass pH to about 4.5 to 6.5 followed by treating with Ν,Ν-dicyclohexylethylenediamine or its acetate salt in a solvent system that does not disturb the course of the reaction. Similarly the Atorvastatin sodium is isolated directly from the reaction mass by treating the residue obtained with solvent selected from acetonitrile, THF, and the like, preferably acetonitrile. To facilitate the filtration of Atorvastatin sodium electrolyte or polymer can be added and optionally co-crystal of Atorvastatin sodium can be isolated by conventional co-crystal methods. Applicant surprisingly found that the isolation of Atorvastatin as Ν,Ν-dicyclohexylethylenediamine salt or as sodium salt having the PXRD pattern as shown in Fig- 1 has purity greater than 99.5%, which indirectly helps to produce the Atorvastatin hemiclacium having purity greater than 99.5%, preferably 99.8%. In still yet another embodiment of the present invention, the novel salt prepared according to the present invention is converted to Atorvastatin hemi calcium salt according the procedure reported in the prior art or by following procedure provided in the examples. Further The isolation of amorphous atorvastatin hemicalcium can be done by removing the solvent from the solution by any desired technique, such as agitated thin film drying, rotational evaporation (such as using a RVD), spin-flash drying, fluid-bed drying, Vacuum tray drying or other techniques known to those skilled in the art.

The starting material of formula (III) used in the present invention is prepared by utilizing the process available in the literature, are following the procedure described in examples from compound of formula (II), and taken in situ manner for the next step. The preparation of (III) is shown as below:

Many other beneficial results can be obtained by applying disclosed invention in a different manner or by modifying the invention with the scope of disclosure.

The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention.

Example-1

Step-A

Preparation of atorvastatin N'N'-dicyclohexylethylenediamine salt

To a solution of (6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- phenylcarbamoyl-pyrrole-l-yl]-ethyl}-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester of formula II (10 g) in methanol (300 mL) was added (25 ml) dilute HC1 (1 : 10) and stirred at 25-30 °C. Reaction mass was concentrated to 20 volume and again 10 volume of fresh methanol added. The reaction mixture was cooled to - 10 °C and added 50 % sodium hydroxide. Temperature was slowly raised to 35-40 °C and stirred. After completion of the reaction, reaction volume was reduced by distillation under vacuum at <40 °C. To the residue was added methanol/water/MTBE and stirred for 30 minutes at 25°-35°C. MTBE layer is separated from the reaction mixture, aqueous layer is again extracted in MTBE. The combined MTBE layer is concentrated along with ethylacetate as co solvent to displace the MTBE solvent. The obtained solution is treated with ethylacetate: water and cooled to 0-5°C. The pH of the solution was adjusted to 5 using 10% HCL at 0-5°C. The separated ethylacetate layer is dried with sodium sulphite and filtered. The dicyclohexylethylenediamine in ethylacetate was slowly added to the filterate at 10°C and stirred for 1 hour at 10°-25°C. The obtained product is filtered and washed with chilled ethylacetate. (Yield: 9gm) Purity >99.64 % by HPLC RS method.

The obtained atorvastatin N'N'-dicyclohexylethylenediamine salt was treated with methanol/water/MTBE mixture and stirred for 30 minutes at 25°-35°C. The pH of the reaction mass was adjusted to 5-5.3 using 10% HCL. To that reaction mass, calcium chloride solution was added and maintained for 10-12 hours. The reaction mixture distilled under vacuum upto 6 to 8 volumes at less than 40°C and maintained for 30 minutes at room temperature. The obtained material was filtered, washed with water and dried under vacuum at 40°C for 24 hours to yield Atorvastatin hemicalcium with purity greater than 99.75%.

Example 2

Preparation of Atorvastatin sodium.

To a solution of (6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- phenylcarbamoyl-pyrrole-l-yl]-ethyl}-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester (10 g) in methanol (250 mL) was added dilute HC1 and stirred at 25°-30 °C. After completion of reaction, the reaction mixture was cooled to -10 °C and added 50 % sodium hydroxide and stirred. After completion of the reaction, reaction volume was reduced by distillation under vacuum. To the residue (or 1 V methanol) was added acetonitrile and stirred, the obtained crystalline material was filtered, washed with acetonitrile and dried under vacuum at 40°C. Purity > 99.7 % by HPLC RS method.

Example 3

Preparation of amorphous Atorvastatin hemiCalcium salt

Method-A

To atorvastatin sodium was added methanol/water/MTBE at 25-30 °C and the pH was adjusted to 7.5-8.5. The reaction mass temperature was raised and followed by addition of calcium chloride solution (0.5 to 0.6 mol). The reaction mass temperature was cooled to 30 °C and stirred. Partially distilled and the precipitated product was filtered and sucks dried to yield amorphous Atorvastatin calcium as described in Fig-3 was dissolved in ethyl acetate at 55-65 °C and water was added over it. Ethyl acetate layer separated and distilled upto 3-7 volume under reduced pressure. Heptane was added slowly in to the solution containing atorvastatin calcium at 25°-30°C (alternatively the reaction mass in ethyl acetate in to heptane). The solid obtained was filtered and washed with n-heptane and dried under vacuum at 40-45°C yielded Atorvastatin calcium in amorphous nature. Purity > 99.78 % by HPLC RS method. (Mobile phase A: Mix 720ml of buffer (Dissolve 1.54 g-of Ammonium acetate in 1000 mL of water. Adjust the pH with Acetic acid to 4.0 ±0.05), 250ml Acetonitrile and 30ml Tetrahydrofuran; Mobile phase B: Mix 230ml of buffer, 700ml Acetonitrile and 70ml Tetrahydrofuran; Flow Rate: 1.3 mL / min; Detection: UV at 245 nm; Injection Volume: 20

Run time : 60 min;

Column Oven Temperature : 30°C) Method-B

To atorvastatin sodium was added methanol/water/MTBE at 25-30 °C and the pH was adjusted to 7.5-8.5 using 50 % HC1 at 20-30 °C. To that was added calcium chloride solution at 20-30 °C and stirred. Reaction mass partially distilled under reduced pressure. To the reaction mass, ethylacetate was added over it and layer separated. Water was added over to the obtained ethylacetate layer at 30°- 40°C, stirred and layer separated. The separated ethylacetate layer was distilled upto 3-7 volume under reduced pressure. Heptane was added slowly in to the solution containing atorvastatin calcium at 25°-30°C (alternatively the reaction mass in ethyl acetate in to heptane). The solid obtained was filtered and washed with n-heptane and dried under vacuum at 40-45°C yielded Atorvastatin calcium in amorphous nature. Purity > 99.65 % by HPLC RS method.

Method-C

Preparation of amorphous atorvastatin hemicalcium from (6-{2-[2-(4- fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrole-l-yll-ethyl}- 2,2-dimethyl-[l,31dioxan-4-yl)-acetic acid tert-butyl ester

To a solution of (6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- phenylcarbamoyl-pyrrole-l-yl]-ethyl}-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester (10 g) in methanol (250 mL) was added dilute HC1 and stirred at 25- 30 °C. After completion of reaction, the reaction mixture was cooled and added 50 % sodium hydroxide and stirred for 20-24 hours at 35°-40°C. After completion of the reaction, reaction volume was reduced by distillation under vacuum. To the obtained solution (solution containing atorvastatin sodium) was added methanol/water/MTBE at 25-30 °C and the pH was adjusted to 7.5-8.5 using 50 % HC1 at 20-30 °C. To reaction mass was added calcium chloride solution at 20-30 °C and stirred. Reaction mass partially distilled under reduced pressure. To the reaction mass, ethyl acetate was added over it and layer separated. Water was added over to the obtained ethylacetate layer at 30°-40°C, stirred and layer separated. The separated ethylacetate layer was distilled upto 3-7 volume under reduced pressure. Heptane, preferably degassed heptane (or hexane, cyclohexane), was added slowly in to the solution containing atorvastatin calcium at 25°-30°C (alternatively the reaction mass in ethyl acetate into heptane). The solid obtained was filtered and washed with n-heptane and dried under vacuum at 40°-45°C yielded Atorvastatin calcium in amorphous nature. Purity ~ 99.3 % by HPLC RS method. Step-D

Preparation of amorphous atorvastatin hemicalcium

The amorphous material obtained from method A or method B or method C was added to methanol (or acetone or ethyl acetate), preferably degassed methanol, at 25-30 °C under stirring and the resulting mixture was degassed by bubbling nitrogen through it, optionally in the presence of butylated hydroxyl anisole and butylated hydroxyl toluene and filtered through hyflow bed. The obtained filterate was concentrated under reduced pressure and then transferred to RVD (Rotatory vacumm dryer) and the amorphous powder obtained was dried further in VTD (Vacuum try dryer) at 40°-45°C. The amorphous atorvastatin hemicalcium obtained is packed under inert condition, i.e. nitrogen atmosphere in a polybags preferably gas non-permeable plastic bags, or metal container or glass container. Step-E

Preparation of amorphous atorvastatin hemicalcium

The amorphous material obtained from method A or method B or method C was added to methanol (or acetone) at 25-30 °C under stirring and the resulting mixture was degassed by bubbling nitrogen through it, optionally in the presence of butylated hydroxyl anisole and/or butylated hydroxyl toluene and filtered through hyflow bed. The obtained filterate was feeded to agitated thin film dryer and dried under vacuum at 35°-45°C. Alternatively the obtained solution was distilled partially transferred to Tray and dried under vacuum at 35°-45°C.

TABLE

NA- Not applicable

Above table indicates the isolation of Atorvastatin as salts of the present invention yields Atorvastatin hemicalcium having purity greater than 99.5%. Reference example

Preparation of (6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- phenylcarbamoyl-pyrrole-l-yl]-ethyl}-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester of formula (II).

To a mixture of 4-fluoro-a-[2-methyl-l-oxopropyl]-y-oxo-N-P-diphenyl- benzenebutanamide and Cis- 1 , 1 -dimethylethyl-6-(2-aminoethyl)-2,2dimethyl- 1,3- dioxane-4-acetate in heptane, pivalic acid was added over it at 25-35 °C. Reaction mass was heated to reflux (100°C) till completion of reaction. After completion of reaction, heptane was distilled out partially and cooled to 65-75°C. The obtained solution was slowly added to isopropanol contain seeded crystal of compound of formula (II) (form- II) at 0-10°C OR to reaction mass in heptane, isopropanol was added followed by optionally seeded with crystal of compound of formula (II) (form-II) at 40-50°C and gradually cooled to 0-10°C. Product was filtered off, washed with chilled isopropanol and dried under vacuum at 50°C.

Claims

ved process for the preparation of Atorvastatin hemicalcium salt rity 99.5%, which comprising the steps of:

hydrolyzing atorvastatin ester of formula (III) using aqueous sodium hydroxide solution in an alcoholic solvent at a temperature in the range of 2 °-50°C ;

(Ill)

ϋ) concentrating the step (i) solution;

iii) isolating the Atorvastatin as N,N-dicyclohexylethylenediamine or as a sodium salt having the PXRD pattern as described in Fig-1; and

iv) converting salts of step (iii) into Atorvastatin of formula (I) as its hemicalcium salt by reacting with calcium source.

(I)

2. A process as claimed in claim 1, wherein alcoholic solvent selected from methanol, ethanol, isopropanol or mixture thereof; preferably methanol.

3. A process as claimed in claim 1, wherein the isolated N,N- dicyclohexylethylenediamine salt of Atorvastatin having a powder X-ray diffraction pattern with peaks at 6.4, 7.7, 9.3, 10.3, 11.0, 12.7, 15.6, 16.0, 16.9, 17.6, 18.7, 19.2, 19.3, 19.8, 20.1, 20.7, 21.0, 22.0, 22.6, 23.0, 23.4,

23.8, 24.5, 24.8, 25.6, 26.0, 26.3, 26.7, 27.1, 27.8, 28.2, 28.5 and 29.3. ± 0.2 degrees 2Θ.

4. A process as claimed in claim 1, wherein N,N-dicyclohexylethylenediamine salt of Atorvastatin is isolated by treating step (ii) reaction mass with N,N- dicyclohexylethylenediamine or its salt in a solvent at pH 4.5 to 7.0.

5. A process of claim 4, wherein solvent used is selected from ethyl acetate, isopropylacetate, dichloromethane, toluene and mixture thereof; preferably ethylacetate.

6. Ν,Ν-dicyclohexylethylenediamine salt of Atorvastatin.

7. Ν,Ν-dicyclohexylethylenediamine salt of Atorvastatin having a powder X- ray diffraction pattern with peaks at 6.4, 7.7, 9.3, 10.3, 11.0, 12.7, 15.6, 16.0,

16.9, 17.6, 18.7, 19.2, 19.3, 19.8, 20.1, 20.7, 21.0, 22.0, 22.6, 23.0, 23.4, 23.8, 24.5, 24.8, 25.6, 26.0, 26.3, 26.7, 27.1, 27.8, 28.2, 28.5 and 29.3. ± 0.2 degrees 2Θ.

8. A process for preparing Ν,Ν-dicyclohexylethylenediamine salt of Atorvastatin comprising reacting Atorvastatin with N,N- dicyclohexylethylenediamine or its salt.

9. A process as claimed in claim 1, wherein the isolated Sodium salt of Atorvastatin is characterized by having a powder X-ray diffraction pattern with peaks at 4.53, 5.53, 5.99, 8.19, 8.64, 9.59, 10.28, 10.62, 11.09, 12.00, 13.08, 13.66, 14.12, 15.26, 16.34, 16.73, 17.38, 17.58, 18.10, 18.54, 19.30, 19.56, 19.94, 20.76, 21.45, 21.92, 22.35, 23.27, 23.62 23.95, 24.45, 24.77, 25.22, 26.54, 26.86, 27.78, 28.07, 28.96, 29.52, 30.03 and 30.70. ± 0.2 degrees 2Θ.

10. Sodium salt of Atorvastatin is characterized by having a powder X-ray diffraction pattern with peaks at 4.53, 5.53, 5.99, 8.19, 8.64, 9.59, 10.28, 10.62, 11.09, 12.00, 13.08, 13.66, 14.12, 15.26, 16.34, 16.73, 17.38, 17.58, 18.10, 18.54, 19.30, 19.56, 19.94, 20.76, 21.45, 21.92, 22.35, 23.27, 23.62 23.95, 24.45, 24.77, 25.22, 26.54, 26.86, 27.78, 28.07, 28.96, 29.52, 30.03 and 30.70. ± 0.2 degrees 2Θ.

11. A process as claimed in claim 1, wherein the Atorvastatin sodium salt is isolated by treating step (ii) reaction mass with acetonitrile or THF.

12. A process for the preparation of Sodium salt of Atorvastatin is characterized by having a powder X-ray diffraction pattern with peaks at 4.53, 5.53, 5.99, 8.19, 8.64, 9.59, 10.28, 10.62, 11.09, 12.00, 13.08, 13.66, 14.12, 15.26, 16.34, 16.73, 17.38, 17.58, 18.10, 18.54, 19.30, 19.56, 19.94, 20.76, 21.45, 21.92, 22.35, 23.27, 23.62 23.95, 24.45, 24.77, 25.22, 26.54, 26.86, 27.78,

28.07, 28.96, 29.52, 30.03 and 30.70. ± 0.2 degrees 2Θ which comprising the steps of: i) hydrolyzing atorvastatin ester of formula (III) using aqueous sodium hydroxide solution in an alcoholic solvent;

ii) concentrating the step (i) solution;

iii) treating the step (ii) mass with an antisolvent isolating the Atorvastatin sodium salt.

13. A process as claimed in claim 12, wherein alcoholic solvent selected from methanol, ethanol, isopropanol or mixture thereof; preferably methanol.

14. A process as claimed in claim 12, wherein antisolvent selected from acetonitrile and THF, preferably acetonitrile.

15. A process as claimed in claim 1, wherein the calcium source used is calcium chloride.