FIELD OF THE INVENTION
Present invention provides a novel process for the preparation of atorvastatin and its calcium salt of Formula I,
.

BACKGROUND OF THE INVENTION
Atorvastatin {[R-(R*,R*)]-2-(4-fluorophenyl)-ß,d-dihydroxy-5-(1-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-1 H-pyrrole-1-heptenoic acid} represented by Figure II, is an inhibitor of the enzyme hydroxy- methylglutaryl coenzyme-A reductase (HMG-CoA-R), which plays a key role in the biosynthesis of cholesterol. The hemi-calcium salt of atorvastatin is useful as an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMG-CoA reductase). By virtue of that activity atorvastatin is an effective antihyper lipoproteinaemic agent and lowers the level of harmful cholesterol in the blood. In that way it contributes to reducing the risk of atherosclerosis and accordingly the risk of infarction and stroke.

U.S 5,124,482 discloses the process for the preparation of atorvastatin including the process for the preparation of 4-fluoro-a-[2-methyl-l-oxopropyl]-?-oxo-N-ß-diphenylbenzenebutanamide by reacting 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentamide with 4-fluorobenzaldehyde in the presence of a catalyst such as 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride, 3, 4-dimethyl-5-(2-hydroxy-ethyl)-thiazolium iodide, 3-ethyl-4-(2-hydroxyethyl)-4-methylthiazolium bromide, thiamine hydrochloride and the base selected from N,N-diisopropylethylamine, pyridine, N,N-dimethylamine, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 4-dimethylaminopyridine, N,N,N',N'-tetramethylethylenedimine.

WO2003/004457 discloses process for the preparation of Atorvastatin and intermediates thereof as mentioned in the scheme below:

.

Further, US 20090209612 discloses another process for the preparation of atorvastatin hemicalcium salt as represented in scheme below:
.

Although there are several processes known from the prior published references, however the known literature suffer from the drawbacks of involving several steps for the preparation of atorvastatin which make the process lengthy and tedious. In view of aforesaid drawbacks, the present invention is focussed in development of new process that involves less number of steps and which is reproducible at large scale production.

OBJECT OF THE INVENTION
The main object of the present invention is to provide a novel process for the preparation of Atorvastatin and its calcium salt.

The another object of the present invention is to provide solid forms of Atorvastatin and its calcium salt wherein said solid form includes crystalline form, amorphous form, and solid dispersion with pharmaceutical acceptable excipients thereof.

SUMMARY OF THE INVENTION
In main aspect, the present invention provides a novel process for the preparation of atorvastatin and its calcium salt.

Accordingly, in one aspect, the present invention provides process for the preparation of atorvastatin hemicalcium salt, wherein said process comprising the steps of:
a) hydrolysing tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula V in a suitable solvent to give tert-butyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate of Formula VII;
; and
b) in situ converting compound of Formula VII to atorvastatin calcium salt of Formula I without isolating said compound of Formula VII,

.

In another aspect, the present invention provides a process for the preparation of atorvastatin hemicalcium salt comprising the steps of:
a) reducing tert-butyl 2-((4R,6R)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula III in presence of reducing agent followed by adding 2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)-4-methyl-3-oxo-N-phenylpentanamide of Formula IV to give tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula V,
;
b) hydrolysing the compound of Formula V to give tert-butyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate of Formula VII and converting said compound of Formula VII to atorvastatin hemicalcium salt in same solvent without isolation of said compound of Formula VII;
; and
c) isolating atorvastatin hemicalcium salt.

In another aspect, the present invention provides a process of preparing atorvastatin hemicalcium salt, wherein said process comprises the steps of:
a) reducing tert-butyl 2-((4R,6R)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula III in presence of reducing agent in a suitable solvent to give a reaction mixture comprising tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula VI,
,
b) adding 2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)-4-methyl-3-oxo-N-phenylpentanamide of Formula IV to the reaction mixture of step (a) in a suitable solvent to give tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula V,
,
wherein compound of Formula VI is not isolated;
c) hydrolysing compound of Formula V in a suitable solvent to give tert-butyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate of Formula VII;

; and
d) converting compound of Formula VII to atorvastatin hemicalcium salt of Formula I without isolating compound of Formula VII,
.

In one another aspect, the present invention provides substantially pure atorvastatin hemicalcium salt wherein said atorvastatin hemicalcium salt is substantially free from impurities with each impurity is less than about 0.3% w/w.

DETAILED DESCRIPTION
Definitions
The term "about" as used in the context of the present invention, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value.

The term “substantially pure” as referred in the context of the present invention relates to substance that has purity preferably between about 95% and 100% by HPLC and total impurities between about 2%w/w to a non-detectable limit, more preferably between about 99% and 100% of purity by HPLC and between about 1%w/w and non-detectable limit of the total impurities, and, most preferably, between about 99.9% and 100% of purity by HPLC and about 0.25%w/w to a non-detectable limit of total impurities.

The term “suitable solvent” as used in the context of the present invention refers to solvents selected from the group comprising of, but not limited to, esters, alcohols, halogenated solvent, nitriles, ketones, hydrocarbons, ethers, sulfoxides, amides, carbonates, water and mixture thereof. Specifically, the suitable solvent is selected from, but not limited to, the group comprising of tetrahydrofuran, 1,4-dioxane, dichloromethane, methanol, ethanol, t-butanol, isopropyl alcohol, dimethyl formamide, dimethyl sulfoxide, chloroform, carbon tetrachloride, hydrocarbons such as n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran; halogenated solvents such as dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride; ketones such as acetone, methyl tert-butyl ketone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; nitriles such as acetonitrile, propionitrile, butanenitrile, sulfoxides, acetamides, water or mixture thereof.

The term "excipient" or "pharmaceutically acceptable excipient" means a component of a pharmaceutical product that is not an active ingredient, and includes but not limited to filler, diluent, disintegrants, glidants, stabilizers, surface active agents etc. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. One excipient can perform more than one function. The term “pharmaceutically acceptable excipient” as used in the context of the present invention, includes, but not limited to, an inorganic oxide such as SiO2, TiO2, ZnO2, ZnO, Al2O3 and zeolite; a water insoluble polymer is selected from the group consisting of cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolat, and cross-linked styrene divinyl benzene, polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90 (PVP K-90), polyvinylpyrrolidone vinylacetate, co-povidone, polyvinyl alcohol, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcellulose and the like; proteins such as gelatin and albumin, cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, and mixture thereof.

The preparation of atorvastatin hemicalcium salt Formula I may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.

In main embodiment, the present invention provides process for the preparation of atorvastatin hemicalcium salt, wherein said process comprising the steps of:
a) hydrolysing tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula V in a suitable solvent to give tert-butyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate of Formula VII;

; and
b) in situ converting compound of Formula VII to atorvastatin calcium salt of Formula I without isolating said compound of Formula VII,

.

In another embodiment, the hydrolysis of compound of Formula V in step a) above is performed in presence of base or acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, PTSA, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide and the like.

In preferred embodiment, the said hydrolysis of compound of Formula V in step a) above is performed in presence of solvent selected from protic solvent such as alcohols, water and mixture thereof.

In a preferred embodiment, the atorvastatin hemicalcium salt is isolated as trihydrate and can be formulated for commercial use.

In another embodiment, the atorvastatin ester of Formula VII is optionally converted to atorvastatin alkali or alkaline earth metal salt followed by conversion of hemicalcium salt of Formula I.

In a preferred embodiment, the atorvastatin alkali or alkaline earth metal salt is represented by Formula IIa,
,
wherein M represents alkali and alkaline earth metals such as sodium, potassium, lithium barium and the like.

In another embodiment, the present invention provides a process for the preparation of atorvastatin hemicalcium salt comprising the steps of:
a) reducing tert-butyl 2-((4R,6R)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula III in presence of reducing agent followed by adding 2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)-4-methyl-3-oxo-N-phenylpentanamide of Formula IV to give tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula V,
;
b) hydrolysing the compound of Formula V to give tert-butyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate of Formula VII and converting said compound of Formula VII to atorvastatin hemicalcium salt in same solvent without isolation of said compound of Formula VII;
; and
c) isolating atorvastatin hemicalcium salt.

In further embodiment, the reduction of tert-butyl 2-((4R,6R)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula III is carried out in presence of reducing agent selected from the group comprising of metal catalyst such as palladium carbon, palladium hydroxide, raney nickel and the like.

In another embodiment, the calcium salt of atorvastatin is isolated as hemicalcium salt. Further, the compound of Formula III and IV are procured from any commercial source or prepared by any known conventional method.

In a preferred embodiment, the present invention provides a process of preparing atorvastatin and its salt by insitu conversion of compound of tert-butyl 2-((4R,6R)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula III to tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula V without isolating intermediate i.e. tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate.

In another aspect, the present invention provides a process for preparing substantially pure atorvastatin hemicalcium salt, wherein said process comprises the steps of:
a) reducing tert-butyl 2-((4R,6R)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula III in presence of reducing agent in a suitable solvent to give a reaction mixture comprising tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula VI,
,
b) adding 2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)-4-methyl-3-oxo-N-phenylpentanamide of Formula IV to the reaction mixture of step (a) in a suitable solvent to give tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula V,
,
wherein compound of Formula VI is not isolated;
c) hydrolysing compound of Formula V in a suitable solvent to give tert-butyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate of Formula VII;

; and
d) converting compound of Formula VII to atorvastatin hemicalcium salt of Formula I without isolating compound of Formula VII,

.

In one another embodiment, the present invention provides a stable atorvastatin hemicalcium which is stable when stored at a temperature of up to about 40oC and at a relative humidity of about 25% to about 75% for about four months and more.

In one another embodiment, the present invention provides a stable and substantially pure crystalline form-1 of atorvastatin hemicalcium salt, wherein said crystalline form is substantially free from amorphous form.

In one another embodiment, the present invention provides a stable and substantially pure amorphous form of atorvastatin hemicalcium salt, wherein said amorphous form is substantially free from crystalline form.

In another embodiment, the present invention provides a process for the preparation of an amorphous form of atorvastatin hemicalcium salt, comprising the steps of:
a) providing a solution of atorvastatin hemicalcium salt in a suitable solvent (s);
b) removing the solvent from the solution obtained in step a) through lyophilization; and
c) isolating the amorphous form of atorvastatin hemicalcium salt.

In one another embodiment, the present invention provides substantially pure atorvastatin hemicalcium salt wherein said atorvastatin hemicalcium salt is substantially free from impurities with each impurity is less than about 0.3% w/w.

In another embodiment, the present invention provides a process for the preparation of a solid dispersion of atorvastatin or its hemicalcium salt, comprising the steps of:
a) providing a solution of atorvastatin or its hemicalcium salt in a suitable solvent(s);
b) adding suitable pharmaceutically acceptable excipient; and
c) isolating solid dispersion of atorvastatin or its hemicalcium salt.

In an embodiment, removal of solvent at step b) may be carried out by methods known in the art or any procedure disclosed in the present invention wherein said method is selected from, but not limited to, solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD), lyophilization and the like. In preferred embodiment, the solvent may be removed under reduced pressures and at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.

In an embodiment, the isolation process of an amorphous form of atorvastatin and its calcium salt includes, but not limited to, techniques such as scraping, adding solvent to make slurry followed by filtration, lyophilization, freeze drying or other techniques specific to the equipment used.

In a preferred embodiment, the present invention provides a solid dispersion of atorvastatin and its hemicalcium salt suitable for powder handling and downstream processes. A solid dispersion of atorvastatin and its hemicalcium salt of the present application was surprisingly found to be highly stable under mechanical stress such as grinding and milling and stable under hygroscopic conditions such as higher relative humidity conditions of more than 60% RH.

In another preferred embodiment, the atorvastatin hemicalcium salt of Formula I is characterized by the particle size distribution wherein, d90 is between 0.1µm to 200µm. More preferably, the atorvastatin hemicalcium salt of Formula I is characterized by particle size distribution wherein, d90 is between 2.0 µm to 150µm.

In still another embodiment, the present invention provides a pharmaceutical composition comprising atorvastatin hemicalcium salt of Formula I prepared as per the process of the present invention along with atleast one pharmaceutical acceptable excipients/ carrier.

In one another embodiment, the present invention provides substantially pure atorvastatin hemicalcium salt wherein said atorvastatin hemicalcium salt is substantially free from impurities with each impurity is less than about 0.3% w/w.

In preferred embodiment, the present invention provides substantially pure atorvastatin hemicalcium salt wherein said atorvastatin hemicalcium salt is substantially free from impurities of Formula A and B, with each impurity is less than about 0.3% w/w.

Formula A

Formula B

In one another embodiment, the present invention provides substantially pure 2-[6-[2-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-(phenyl carbamoyl) pyrrol-1-yl] ethyl]-2, 2-dimethyl-1, 3-dioxan-4-yl] acetate of Formula V in high yields wherein diamino impurity is less than about 0.05%.

Further, the process is economical as only single solvent is used for preparing intermediates.

Moreover, higher purity and quality of atorvastatin hemicalcium is obtained as all impurities are below 0.07% w/w.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference of the following examples, which are provided only for purposes of illustration and should not able constructed as limited the scope of the application in any manner.

EXAMPLES:
EXAMPLE 1: Preparation of tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula V:

Charged tert-butyl 2-((4R,6R)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula III (100.0 g) was charged in Hydrogenator. Cyclohexane (800 mL) and aq. ammonia solution (90 ml) were added at ambient temperature and the reaction mass was stirred for 8 hours under H2 pressure 5.0-6.0 Kg/cm2 at 30-60°C. Reaction progress was checked by TLC. After reaction completion catalyst was removed by filtration through hyflo bed and bed washed with cyclohexane (50 ml). Aqueous layer was separated and organic layer forward to next step as such. Added Pivalic acid (36.0 g, 0.352 mol) and 2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)-4-methyl-3-oxo-N-phenylpentanamide (150.0 g, 0.359 mol) of Formula IV to the organic layer at RT. Added di isopropyl amine (36.0 g 0.356 mol) and tetra butyl ammonium hydrogen sulphate (19.0 g, 0.056 mol) and refluxed till completion of reaction. Water is removed azeotropically. Reaction mass is diluted with aqueous sodium carbonate solution. Separated the layers and distilled the organic layer under vacuum. Residue purified in IPA and water then filtered. Wet compound is again purified in IPA and dried to get desired compound (201.0 g, Purity: 98.5%).
Diamino impurity below 0.05%.

EXAMPLE 2: Preparation of atorvastin hemicalcium salt:
tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (100.0 g, 0.152 mol) of Formula V is reacted with hydrochloric acid in Methanol (1000 mL) and DMW and stir at 30-50°C for de-protection of diol. After completion of reaction, add Aqueous NaOH solution (pH: 12-14) to the reaction mass and stirred at 40-60°C. After completion of hydrolysis, reaction mass is distilled and diluted with water (1000.0 mL), methanol (200 mL) and tert butyl methyl ether (500 mL). Reaction mixture was stirred at 25-45°C, and layers were separated. Solution of calcium acetate (14.5 g, 0.091 mol) in water (1000 mL) and Form-I seed were added to aqueous layer at 40-60°C. pH of reaction mass was adjusted 8.5-8.8 using acetic acid. Reaction mass was stirred, cooled and filtered. Wet compound was charged in ethyl acetate: cyclohexane (1:1) (1000 ml), stirred at 45-75°C, cooled to RT and then filtered. Wet compound was charged in water (500 ml), stirred at 30-50°C, cooled to RT and then filtered. Solid was dried under vacuum to get Atorvastatin Calcium (85.0 g, Purity: 99.7%)
Diamino impurity below 0.05%

EXAMPLE 3: Preparation of atorvastin hemicalcium salt:
2-[6-[2-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-(phenyl carbamoyl) pyrrol-1-yl] ethyl]-2, 2-dimethyl-1, 3-dioxan-4-yl] acetate (100.0 g, 0.152 mol) was reacted with aq. hydrochloric acid solution in Methanol (1000 mL) and DM water (100 mL) and stirred at 30-50°C for de-protection of diol. After completion of deprotection, reaction mass was concentrated up to 50% volume, and then methanol (500 mL) was added. 10 % aqueous NaOH solution (200 mL) was added to the reaction mass (pH: 12-14) and stirred at 40-60°C. After completion of hydrolysis, reaction mass was treated with carbon, and distilled and diluted with water (1000.0 mL), methanol (200 mL). MTBE (100 mL) was charged in reaction mass and stirred at 40-60°C. Solution of calcium acetate (14.5 g, 0.091 mol) in water (1000 mL) and Form-I seed were added to aqueous layer at 40-60°C. pH of reaction mass was adjusted 8.5-8.8 using acetic acid. Reaction mass was stirred, cooled and filtered. Wet compound was charged in ethyl acetate and cyclohexane (1:1) (1000 ml), stirred at 45-75°C, cooled to RT and then filtered. Wet compound was charged in water (500 ml), stirred at 30-50°C, cooled to RT and then filtered. Solid was dried under vacuum to get Atorvastatin Calcium (90.0 g, Purity: 99.6%)
Diamino impurity below 0.05%

CLAIMS:WE CLAIM
1. A process for the preparation of atorvastatin and its calcium salt, wherein said process comprising the steps of:
a) hydrolysing tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula V in a suitable solvent to give tert-butyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate of Formula VII;
; and
b) in situ converting compound of Formula VII to atorvastatin calcium salt of Formula I without isolating said compound of Formula VII,

.

2. The process as claimed in claim 1, wherein said hydrolysis of compound of Formula V in step a) is performed in presence of base or acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, PTSA, sodium hydroxide, potassium hydroxide, calcium hydroxide, and lithium hydroxide.

3. A process for the preparation of atorvastatin hemicalcium salt comprising the steps of:
a) reducing tert-butyl 2-((4R,6R)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula III in presence of reducing agent followed by adding 2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)-4-methyl-3-oxo-N-phenylpentanamide of Formula IV to give tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula V,
;
b) hydrolysing the compound of Formula V to give tert-butyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate of Formula VII and converting said compound of Formula VII to atorvastatin hemicalcium salt in same solvent without isolation of said compound of Formula VII;
; and
c) isolating atorvastatin hemicalcium salt.

4. The process as claimed in claim 3, wherein said reducing agent is selected from the group comprising of metal catalyst.

5. The process as claimed in claim 1 and 3, wherein said solvent is selected from the group comprising of hydrocarbons; esters, ethers, halogenated solvents, ketones, nitriles, sulfoxides, acetamides, alcohols, water or mixture thereof.

6. A process for preparing substantially pure atorvastatin hemicalcium salt, wherein said process comprises the steps of:
a) reducing tert-butyl 2-((4R,6R)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula III in presence of reducing agent in a suitable solvent to give a reaction mixture comprising tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula VI,
,
b) adding 2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)-4-methyl-3-oxo-N-phenylpentanamide of Formula IV to the reaction mixture of step (a) in a suitable solvent to give tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula V,
,
wherein compound of Formula VI is not isolated;
c) hydrolysing compound of Formula V in a suitable solvent to give tert-butyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate of Formula VII;

; and
d) converting compound of Formula VII to atorvastatin hemicalcium salt of Formula I without isolating compound of Formula VII,

.

7. The process as claimed in claim 6, wherein said atorvastatin hemicalcium salt is characterized by purity above 99.0%, and is substantially free from impurities with each impurity is less than about 0.3% w/w.

8. A stable atorvastatin hemicalcium salt, wherein said atorvastatin hemicalcium is stable when stored at a temperature of up to about 40oC and at a relative humidity of about 25% to about 75% for about four months and more.

9. Atorvastatin hemicalcium salt as obtained in any of the preceding claim is characterized by particle size distribution D90 less than about 200µm.

10. A process for the preparation of solid dispersion of atorvastatin or its hemicalcium salt, comprising the steps of:
a) providing a solution of atorvastatin or its hemicalcium salt in a suitable solvent(s);
b) adding suitable pharmaceutically acceptable excipient; and
c) isolating solid dispersion of atorvastatin or its hemicalcium salt.