Title of Invention

"AN IMPROVED PROCESS FOR THE PREPARATION OF AMORPHOUS [R(R*,R*)-2-(4-FLUORO PHENYL), P S, DIHYDROXY-5-(1-METHYL ETHYL)-3-PHENYL-4-[(PHENYL AMINO)CARBONYL)-1H-PYRROLE-1-HEPTANOIC ACID HEMI EALCIUM SALT (ATORVASTATIN CALCIUM SALT)"

Abstract The objective of the invention is to provide an efficient and alternative process for the preparation of amorphous atorvastatin calcium salt, which eliminates the problems of prior art and is convenient to operate on a commercial scale, and also involves ecofriendly process over the prior art. The present invention provides the improved process for the preparation of amorphous atorvastatin calcium, which comprises dissolving crystalline or blend of crystalline or mixture thereof including amorphous atorvastatin calcium in ester solvents preferably ethyl acetate followed by removal of solvent by spray drying or Ultrafilm agitated thin film drying- vertical (ATFD-V), further drying under vaccum to get amorphous atorvastatin calcium. The process for the production of amorphous form of Atorvastatin involves one step conversion of [R-(R*, R*)]-2-(4-fluorophenyl)-P, 8-dihydroxy -5- (1-methylethyl) -3-phenyl-4-[(phenyl amino)-carbonyl]-lH-pyrrole-l-heptanoic acid, tertiary butyl ester, (hereinafter referred to as "ester" for convenience) to amorphous form of Atorvastatin calcium via crude Atorvastatin calcium .
Full Text

AN IMPROVED PROCESS FOR THE PREPARATION OF AMORPHOUS [R-(R*,R*)-2-(4.FLUOROPHENYL)-p,5 DIHYDROXY-5-(l-METHYL ETHYL)-3-PHENYL-4"[(PHENYL AMINO)CARBONYL)-lH-PYRROI.F-l-HEPTANOir ACID HEMI CALCIUM SALT (AMORPHOUS ATORVASTATIN CALCIUM)
FIELD OF INVENTION
The present invention relates to an improved process for the preparation of amoiphous
[R-(R*, R*)]-2-(4-fluorophenyl)-p, 5-dihydroxy-5-(l-methylethyl)-3- phenyl-4- [(phenyl amino)carbonyl]-lH-pyrrole-l-heptanoic acid hemi calcium salt (Amorphous Atorvastatin calcium salt), which is represented by the following Figurel.

BACKGROUND OF THE INVENTION
The present invention relates to pro'cess for the preparation amoiphous Atorvastatin calcium salt which is known by the chemical name [R-(R*, R*)]-2-(4-fluorophenyl)-p, 5-
dihydroxy-5-(l-methylethyl)-3- phenyl-4- [(phenyl amino)carbonyl]-lH-pyn'ole-l-heptanoic acid hemi calcium salt.
United States Patent 5, 273, 995, describes that R-form of Ihc ring opened acid Ibnn inhibits the biosynthesis of cholesterol. Atorvastatin in its calcium saU form, i.e.

amorphous[R- (R*, R*) ]- 2-(4-fluorophenyl)-ss, 6-dihydroxy-5-(I-melhylethyl)-3-phenyl-4-[(phenylamino) carbonyl3-l H-pyn-ole-t-heptanoic acid hemi calcium sail (2:1) is discussed in literature.
PCT application, WO 97/03960, describes a procedure for converting crystalline form of Atorvastatin to amorphous foirn. Process disclosed therein describes dissolving crystalline Atorvastatin in non-hydroxylic solvent like tetrahydrofuran or mixtures of tetrahydrofuran and toluene. The process involves complete removal of solvent under high temperature (about 90^^C) and high vacuum (about 5 mm) using capital-intensive equipment. Exposure of the material for several days leads to the degradation of the product. This renders the process inconvenient to operate at a large scale. Slow removal of the solvents at a manufacturing scale makes the process less cost effective and productive. Furthermore the amorphous form disclosed in this patent has drawback, as it contains high Residual Solvent content like toluene and tetrahydrofuran even after 4 days drying, use or distillation of tetrahydrofuran at commercial scale may result in hazardous as explosion.
PCT application, WO 00/71116 Al discloses a process for the preparation of amorphous form of Atorvastatin calcium. The process involves dissolving crystalline Atoi-vastatin calcium in tetrahydrofuran at ambient temperature and regeneration of the compound by adding an anti-solvent such as n-hexane, n-heptane and cyclohexane. The disadvantage of the above process is primarily the use of environmentally unsound solvents. Furthermore, it involves the usage of mixture of solvents which is not effective process at scale-up, as the column distillation is required to recycle the solvent thus rendering the process high manufacturing cost apart from being dangerous.

PCT application, WO 01/28999 Al discloses a process for the preparation oi' amorphous form of Atorvastatin calcium. The patent describes the process for the preparation of amorphous foim of Atorvastatin calcium by recryslaili/alioii of crude Atorvastatin, which comprises dissolving the crude Atorvastatin in isopropanol or ethanol or a mixture of both at boiling point of the solvent and isolation by filtering the precipitated amorphous form of Atoi-vastatin at low temperature. The process involves the usage of mixture of solvents, high volume of solvents and hence the process is not cost effective at commercial scale.
PCT application, WO 01/42209 discloses a process for the preparation of amorphous form of Atoi*vastatin starting from Atorvastatin, which comprises dissolving the compound in Type-I solvent (i.e, freely soluble solvent) and regenerating the amoi-phous form of Atorvastatin by adding Type-II solvent (i.e, sparingly soluble or insoluble solvent). The disadvantage of the process is the conversion of crystalline Atorvastatin to amorphous form of Atorvastatin, that indicates firstly the generation of crystalline Atorvastatin, which in turn is converted to amorphous form of Atorvastatin. PCT application, WO 02/059087 Al discloses a process for preparation of noncrystalline form of Atorvastatin calcium salt, which comprises dissolving the intermediate of atorvastatin in non-hydroxylic solvent and the protected groups were hydrolyzed using HCl followed by NaOH, and after completion of the reaction the solution was concentrated under vaccume, and made the calcium salt, and after stirring for 1 hour placed in the refrigerator for 2 hours, formed precipitate was filtered and dried to get the amorphous atorvastatin calcium salt, the disadvantage of this invention is slow conversion to the noncrystalline form, that is conversion of dihydroxy protected

and carboxylic acid protected compound to atorvastatin is slow, and drying involves more time.
PCT application, WO 03078379 Al discloses a process for preparation of Atorvaslatin calcium which involves, heterogeneous mixture of atorvastatin added to methanol and resulting mixture was freeze dried or spray dried to get the amorphous form, the disadvantage of this process is freeze drying is very difficult to perform on large scale. PCT application, WO 03/018547 A2 discloses a process for the preparation of amoiphous form of Atorvastatin calcium salt which involves, dissolution of crystalline atorvastatin calciuni in solvent like methylene chloride and after concentrating the reaction mass filtered and added to precooled diisopropylether and after completing the addition, filtered product and dried under vaccume to get the amorphous form. The disadvantage of this process is the usage of chloro solvent which are not ecofriendly and the conversion of crystalline foiTn into amorphous foim, indicates firstly the generation
of crystalline Atorvastatin calcium salt which in turn converted to amorphous atorvastatin calcium salt.
PCT application, WO 03/068739 Al discloses a process for the preparation of amorphous form of atorvastatin calcium salt, which involves hydrolysis of dihydroxy protected and carboxylic acid protected atorvastatin in acidic hydrolysis followed by alkaline hydrolysis and after optional acidification and extracted with solvent and made calcium salt and later precipitated and obtained compound dried under vaccume to get the amorphous atorvastatin calcium salt, the disadvantage of this process is multistcps arc involved in the synthesis of amoiphous atorvastatin calcium salt, and this process is not suitable for pharma application.

wo 02083637 Al discloses a process for the preparation o( amorphous alorvastaiin
calcium salt, which comprises suspension of diol protected tert butyl ester in methanol
and hydrolysed the both protecting groups using acidic and basic conditions and after
completion of the reaction the P" adjusted to 8.5 and concentrated the reaction mixlurc
and added specified volumes of methanol and water, washed with diisopropyl ether and
made Calcium salt using calcium chloride solution, and filtered and dried to get the
amorphous atorvastatin calcium salt, the disadvantage of this invention is specific ratio of
methanol and water are to be maintained which is difficult in industrial scale up.
Nevertheless, the process for the production of amorphous atorvastatin calcium salt is desirable.
SUMMARY OF THE INVENTION
The objective of the invention is to provide an efficient and alternative process for the
preparation of amorphous atorvastatin calcium salt, which eliminates the problems oi^ prior art and is convenient to operate on a commercial scale, and also involves ecofriendly process over the prior art.
The present invention provides the improved process for the preparation of amorphous atoi-vastatin calcium, which comprises dissolving crystalline or blend of crystalline or mixture thereof including amorphous atorvastatin calcium in ester solvents preferably ethyl acetate followed by removal of solvent by spray diying or Ultrafilm agitated thin film drying- vertical (ATFD-V), further drying under vaccum to get amorphous atoi-vastatin calcium.

The process for the production of amorphous form of Atorvastatin involves one step conversion of [R-(R*, R*)]-2-(4-fluorophenyl)-(3, 6-dihydroxy -5- (1-methylethyl) -3-plienyl-4-[(plienyl amino)-carbonyl]-1 li-pyrrole-l-heplanoic acid, tertiary hutyl ester, (hereinafter referred to as "ester" for convenience) to amorphous form of Atorvastatin calcium via crude Atorvastatin calcium . BRIEF DESCRIPTION OF ACCOMPANYING DRAWING
Fig. 1 is a characteristic X ray powder diffractogram of amorphous form of Atorvastatin calcium.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention is the improved and alternative process for the preparation of [R-
(R\ R*)]-2-(4-fluorophenyl)-(3, 5-dihydroxy-5-(l-methylethyl)-3- phenyl-4- [(phenyl amino)carbonyl]-lH-pyrrole-l-heptanoic acid hemi calcium salt (Amorphous Atorvastatin calcium), using readily available solvents and can be produced on industrial basis.
The present invention provides the improved process for the preparation ol'amorphous atorvastatin calcium, which comprises:
a) dissolving crystalline or blend of crystalline or mixture thereof including
amorphous atorvastatin calcium in ester solvents preferably ethyl acetate.
b) removing the solvent by spray drier or Ultrafilm agitated thin film dryer- vertical
(ATFD-V);
c) the compound obtained in step b) micronized and dried under vaccume or air to
get amorphous atorvastatin calcium .

The present invention also provides improved process for the preparation of amorphous atorvastatin calcium, which comprises:
a) heating [R-(R*, R*)]-2-(4-fluorophenyl)-p, 8-dihydroxy -5-( 1 -methyl ethyl)-3- phenyl-4-[(phenyl amino)-carbonyl]-lH-pyn-ole-l-heptanoic acid, tertiary butyl ester, (hereinafter referred to as "cslcr" lor convenience) , acetonitrile and sodium hydroxide and water to about 25-60°C;
b) maintaining the reaction mixture of step a) at 25-60°C for about 2-6 hours preferably 3 hours;
c) adding to the above reaction mixture an aqueous solution of calcium acetate hemihydrate and 10%NaOH solution;
d) further stirring the reaction mixture at 20-70°C for about 30 minutes to 2 hours;

e) filtering the reaction solution obtained in step d) through hyflow bed;
f) distilling the solvent from reaction solution of step e) to yield a residue and dissolving the residue with ethyl acetate or a mixture of ethyl acetate and acetonitrile or extracting reaction solution of step e) in a ethyl acetate
g) feeding the organic layer into Spray drying or Ultrafilm agitated thin Film dryer- vertical (ATFD-V)
h) micronzing the powder obtained in step g) and dying under vacuum or air to get amorphous atorvastatin. In step a) of the process an ester with an alkyl group of 1-10 carbon atoms, allyl or bcn/yl group can be used in place of the tertiary butyl ester and another nitrile such as

propionitrile can be used in place of acetonitrile. The ratio of solvent to active ingredient
in step a) is 4-10,preferably 8 times the active ingredient (wt: volume) (gm: ml).
In step a) the molar ratio of active ingredient to base is 1: 1-1.5 preferably 1: 1.15.
In step a) other alkali hydroxides can be used in place of sodium hydroxide. The alkali
hydroxides including the sodium hydroxide may be in any form and the fomi is not
limited to flakes.
The following organic and inorganic salts of calcium may be used in place of calcium
acetate hemihydrate :
Organic salts such as carboxylates and sulphonates. The carboxylates may be selected
from acetate, propionate, butyi'ate, tartarate; aryl carboxylates like benzoate and phthlate
as well as higher carboxylates like Stearate or dodecanoate. Also included are succinate
and ascorborate.
Sulphonates may be selected from lower alkyl and aryl sulfonates like calcium methane
sulfonates, calcium benzene sulfonates and calcium para toluenesulfonates.
Inorganic salts of calcium may be selected from calcium chloride, lluoridc, bromide,
iodide and calcium borate and tetra fluoro borate, calcium carbonate, mono, di and tri
basic calcium phosphate, calcium sulfate and calcium hydroxide and hydrates thereof.
The molar ratio of active ingredient to calcium acetate hemihydrate or calcium salt is 1:
0.5-0. 7 preferably 1:0.6.
Moreover, the HPLC purity of amorphous Atorvastatin calcium of the present invention
is greater than 99.0% ,more preferably greater than 99.6%.
EXAMPLES

The present invention is illustrated by the following examples, which are not intended to
limit the effective scope of the invention.
Example: 1
A mixture of [R-(R*, R*)]-2-(4-tluoro phenyl)-p,5 dihydroxy -5-[(l-methyl ethyl)-3-
phenyl- 4-[(phenyl amino)-carbonyl] -1 H-pyrrole-1 -heptanoic acid, tert, butyl ester
(450.Ogr), acetonitrile (3600ml), water (1125 ml) and sodium hydroxide flakes (32.2gr)
are heated to about 25-55°C and maintained at the same temperature for about 3hrs. To
the reaction mixture is then added an aqueous solution of calcium acetate hemihydrale
(72.Og in 720 ml of water) and 10%NaOH solution (17 ml) stirred at 30-50V for about 1
hour. Subsequently, the solution obtained is filtered through hyflow bed and washed with
acetonitrile (450 ml). The solvent is then distilled completely to yield residue, ^fo the
residue thus obtained, ethyl acetate (.8000ml) is added and the reaction mixture was
filtered. Organic layer was feeded to the Ultrafilm agitated thin film dryer- vertical
(ATFD-V) or Spray drier and obtained powder was micronized and dried under vacuum
or air to get Atorvastatin Calcium Amorphous (340gr).
Purity: 99.8%
Example: 2
Dissolve crystalline form (Form-I or Form-Q) of Atorvastatin Calcium (200gr) in ethyl
acetate (2000 ml) and filter the reaction mass through high flow. Feed the organic layer into Ultrafilm agitated thin film dryer- vertical (ATFD-V) or spray drier and obtained powder was micronized and dried under vacuum or air to get Atoi-vastatin Calcium Amoiphous(160 gr)
Purity: 99.8%

Example: 3
A mixture of [R-(R*, R*)]-2-(4-nuoro phenyl)-p,8 dihydroxy -5-|( 1-methyl cthyl)-3-
phenyl- 4-[(phenyl amino)-carbonyl] -lH-pyrrole-1-heptanoic acid, tert. butyl ester (ISO.Og), acetonitrile (1200ml), water (375ml) and sodium hydroxide flakes (10.7g) arc heated to about 25-"55°C and maintained at the same temperature for about 2 to 3 hours. To the reaction mixture is then added an aqueous solution of calcium acetate hcmihydrale (24.0gr in 240,0 ml of water) and 10%NaOH solution (7.5ml), stirred at 30-50T for about 1 hour. Subsequently, the solution obtained is filtered through hyflow bed and washed with acetonitrile (125 ml). Then extracted the reaction mass with ethyl acetate (2800 ml) and washed the organic layer with water (pH: 7-8). Organic layer was feeded into Ultralllm agitated thin film dryer- vertical (ATFD-V) or spry drier and obtained powder was micronized and dried under vacuum or air to get Amorphous Atorvastatin Calcium (1 lOgr).
Purity: 99.8%
DETAILED DESCIPTION OF ACCOMPANYING DRAWING
Amorphous Atorvastatin calcium prepared according to the process of the present invention may be characterized by its X-ray powder diffraction pattern (Figure 1). X-ray powder diffraction pattern (Figure 1) show no significant peaks, which is characteristic of amorphous Form.
The X-Ray diffraction patterns of amoiphous foim of Atorvastatin calcium was measured Bruker Axe, D8 Advance Powder X-ray Diffractometer with Cu K alpha-1 Radiation source.
Vertical axis: Intensity (GPS); Horizontal axis: Two Theta (degrees).



WE CLAIM:
1. A process for the preparation of amorphous atorvastatin calcium, which comprises
a) dissolving crystalline or blend of crystalline or mixture thereof including
amorphous atorvastatin calcium in ester solvents preferably ethyl acetate.
b) removing the solvent by spray drier or Ultrafilm agitated thin film dryer- vertical (ATFD-V);
c) the compound obtained in step b) was micronized and dried under vaccume or air to get amorphous atorvastatin calcium salt.
2. A process for the preparation of amorphous atorvastatin calcium, which comprises:
a) heating [R-(R*, R*)]-2-(4-fluorophenyl)-P, 8-dihydroxy -5- 1 -(methyl
ethyl)-3- phenyl-4-[(phenyl amino)-carbonyl]-lH-pyrrole-l-heptanoic
acid, tertiary butyl ester, acetonitrile and sodium hydroxide and water to
about 25-60°C;
b) maintaining the reaction mixture of step a) at 25-60'^C for about 2-6 hours preferably 3 hours;
c) adding to the above reaction mixture an aqueous solution of calcium acetate hemihydrate and 10%NaOH solution;
d) further stimng the reaction mixture at 20-70°C for about 30 minutes to 2 hours;
e) filtering the reaction solution obtained in step d) through hydow bed;
0 distilling the solvent from reaction solution of step c) to yield a residue and dissolving the residue in ethyl acetate or a mixture of ethyl acetate and acetonitrile or extracting reaction solution of step e) with ethyl acetate

g) feeding the organic layer into Spray drying or Ultrafilm agitated thin
film dryer- vertical (ATFD-V) h) micronzing the powder obtained in step g) and dying under vacuum or
air to get amorphous atorvastatin.


Documents:

863-CHE-2003 FORM-18.pdf

863-CHE-2003 AMENDED CLAIMS 20-09-2011.pdf

863-CHE-2003 AMENDED PAGES OF SPECIFICATION 20-09-2011.pdf

863-CHE-2003 CORRESPONDENCE OTHERS 20-09-2011.pdf

863-CHE-2003 FORM-3 20-09-2011.pdf

863-che-2003-abstract.pdf

863-che-2003-claims.pdf

863-che-2003-correspondnece-others.pdf

863-che-2003-description(complete).pdf

863-che-2003-description(provisional).pdf

863-che-2003-drawings.pdf

863-che-2003-form 1.pdf

863-che-2003-form 5.pdf


Patent Number 250705
Indian Patent Application Number 863/CHE/2003
PG Journal Number 04/2012
Publication Date 27-Jan-2012
Grant Date 20-Jan-2012
Date of Filing 28-Oct-2003
Name of Patentee DR. REDDY'S LABORATORIES LIMITED
Applicant Address 7-1-27, AMEERPET, HYDERABAD, AP, 500 016.
Inventors:
# Inventor's Name Inventor's Address
1 SUNDARAM VENAKATRAMAN DR. REDDY'S LABORATORIES LIMITED, 7-1-27, AMEERPET, HYDERABAD, AP, 500 016.
2 GUDIPATI SRINIVASULU DR. REDDY'S LABORATORIES LIMITED, 7-1-27, AMEERPET, HYDERABAD, AP, 500 016.
3 KATKAM SRINIVAS DR. REDDY'S LABORATORIES LIMITED, 7-1-27, AMEERPET, HYDERABAD, AP, 500 016.
4 KOMATI SATYANARAYANA DR. REDDY'S LABORATORIES LIMITED, 7-1-27, AMEERPET, HYDERABAD, AP, 500 016.
5 VIKAS NAGPAL DR. REDDY'S LABORATORIES LIMITED, 7-1-27, AMEERPET, HYDERABAD, AP, 500 016.
PCT International Classification Number A61K31/40
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA