FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13]

1. Title of the invention: "An improved process for the preparation of Amorphous Atorvastatin Calcium1'
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road; Andheri
I (East), Mumbai - 400 059, Maharashtra, India.
3. The following specification describes the invention.

AN IMPROVED PROCESS FOR THE PREPARATION OF AMORPHOUS
ATORVASTATIN CALCIUM
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of storage stable amorphous atorvastatin calcium comprises treating atorvastatin calcium with aqueous ammonia solution and isolating storage stable amorphous atorvastatin calcium.
BACKGROUND OF THE INVENTION
U.S. Patent No. 4,681,893, which is herein incorporated by reference, discloses certain trans-6-[2-(3- or 4-carboxamidosubstituted-pyrrol-l-yl)alkyl]-4-hydroxy-pyran-2-ones including trans (±)-5-(4-fluorophenyl)-2-(l-methylethyl)-N,4-diphenyl-l-[(2-tetrahydro- 4-hydroxy-6-oxo-2H-pyran-2-yl)ethyI]-lH-pyrrole-3-carboxamide.
U.S. Patent No. 5,273,995, which is herein incorporated by reference, discloses the
enantiomer having the R form of the ring-opened acid of trans-5-(4-fluorophenyl)-2-(l-
methyIethyl)-N,4-diphenyl-l-[(2-tetrahydro-4 -hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-lH-
pyrrole-3-carboxamide, i.e., [R-(R*,R*)]-2-(4-fluorophenyl)-p,5-dihydroxy-5-(l-
methylethyl)- 3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid.
Atorvastatin calcium, a synthetic HMG-CoA reductase inhibitor, is chemically calcium salt
of [R-(R*,R*)]-2-(4-fluoro-phenyl)-p dihydroxy-5-(l-methylethyl)-3-phenyl4-
[(phenylamino) carbonyl]-lH pyrrole-1-heptanoic acid and is used for the treatment of hyperlipidemia and hypercholesterolemia, both of which are risk factors for arteriosclerosis and coronary heart disease.
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U.S. Patent Nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,248,793; 5,280,126; 5,342,952, which. are herein incorporated by reference, describe various processes and key intermediates for preparing atorvastatin.
Atorvastatin calcium produced by the processes described in the above mentioned United States patents does not give amorphous atorvastatin consistently but gives a mixture of its crystalline and amorphous forms, which has unsuitable filtration and drying characteristics and are not suitable for large-scale production.
PCT application WO 97/03960 describes a procedure for converting the crystalline form of atorvastatin to the amorphous form. Process disclosed therein comprises dissolving crystalline form-I atorvastatin in a non-hydroxylic solvent Uke tetrahydrofuran or mixtures of tetrahydrofuran and toluene. The process involves complete removal of the solvent under high temperature (about 90° C.) and high vacuum (about 5 mm) using capital intensive equipment. Exposure of the material to high temperature for several days leads to degradation of the product. This makes the process very inconvenient to operate at a large scale. Slow removal of solvents at a manufacturing scale renders this process as inefficient cost-wise and less productive.
U.S. Patent No 6,528,660 describes a process for the preparation of amorphous atorvastatin calcium and hydrated thereof. Process disclosed therein comprises dissolving crystalline atorvastatin calcium in a non-hydroxylic solvent followed by adding a non-polar hydrocarbon antisolvent or adding the dissolved atorvastatin to the non-polar anti-solvent to precipitate out atorvastatin calcium and removing the solvent by filtration to afford amorphous atorvastatin calcium.
U.S. Patent Nos. 6,613,916; 6,891,047; 6,750,353; 6,646,133; 7,074,940; 7,230,120; 7,161,012; 7,151,183; 7,189,861; 7,208,608 which are herein incorporated by reference, describe various processes for preparing amorphous atorvastatin calcium.
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Atorvastatin calcium produced by the processes described in the above mentioned references does not produce storage stable amorphous atorvastatin calcium and oxidative degradation impurities such as 4-[6-(4-Fluoro-phenyl)-6-hydroxy-lb-isopropyl-6a-phenyl-la-phenylcarbamoyl-hexahydro-L 2-dioxa-5a-aza-cycIopropa[a]inden-3-yl]-3-(R)-hydroxy-butyric acid; 4-(4-Fluoro-phenyl)-2, 4-dihydroxy-2-isopropyl-5-pheny]-3, 6-dioxa-bicyclo [3.1.0] hexane-1-carboxylic acid phenylamide and4-[lb-(4-Fluoro-phenyl)-6-hydroxy-6-isopropyl-la-phenyl-6a-phenylcarbamoyl-hexahydro-l, 2-dioxa-5a-aza-cyclopropa[a]inden-3-yl]-3-(R)-hydroxy-butyric acid are encountered during stability studies.
U.S Patent Publication No 2007/0208071 describes that when atorvastatin calcium or a pharmaceutical formulation containing atorvastatin calcium in the form of tablets are stored in air atmosphere at the room temperature for 24 months oxidative degradation products dramatically increases and this can be avoided when atorvastatin calcium is stored in a nitrogen atmosphere.
European Patent Application No 1659110 describes the use of an antioxidant such as butylated hydroxyanisole, butylated hydroxytoluene and tertiary butylated hydroquinone to obtain stabilized amorphous atorvastatin calcium.
Storage of atorvastatin calcium in a nitrogen atmosphere and use of antioxidant to obtain stabilized amorphous atorvastatin calcium are one of the limitations which make amorphous atorvastatin calcium inconvenient and unsuitable for formulation and therefore there is a need in the art to develop an improved process for the preparation of storage stable amorphous atorvastatin calcium.
SUMMARY OF THE INVENTION
It is an objective of the present invention to provide an improved process for the preparation of storage stable amorphous atorvastatin calcium comprises the treating
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atorvastatin calcium with aqueous ammonia solution and isolating storage stable amorphous atorvastatin calcium.
DETAILED DESCRIPTION OF THE INVENTION
Atorvastatin calcium used in the present invention may be produced by processes known in the literature such as those described in U.S. Patent Nos. 5,273,995; 5,969,156; 6,605,729; 6,121,461; 6,605,636; 6,528,660; 6,613,916; 6,891,047; 6,750,353; 6,646,133; 6,087,511; 6,274,740; 7,074,940; 7,230,120; 7,161,012; 7,151,183; 7,189,861; 7,208,608; 7144916; 7256212; 7411075 which are herein incorporated by reference.
Atorvastatin calcium used in the present invention may be in crystalline form or in amorphous form.
Atorvastatin calcium used in the present invention may contain 0.2% weight / weight to 1% weight / weight of oxidative degradation impurities such as 4-[6-(4-Fluoro-phenyl)-6-hydroxy-1 b-isopropyl-6a-phenyl-1 a-phenylcarbamoyl-hexahydro-1, 2-dioxa-5a-aza-cyclopropa[a]inden-3-yl]-3-(R)-hydroxy-butyric acid; 4-(4-Fluoro-phenyl)-2, 4-dihydroxy-2-isopropyl-5-phenyl-3, 6-dioxa-bicyclo [3.1.0] hexane-1-carboxylic acid phenylamide and 4-[lb-(4-Fluoro-phenyl)-6-hydroxy-6-isopropyl-la-phenyl-6a-phenylcarbamoyl-hexahydro-l,2-dioxa-5a-aza-cyclopropa[a]inden-3-yl]-3-(R)-hydroxy-butyric acid.
Atorvastatin calcium may be treated with aqueous ammonia solution in an organic solvent to get a hazy solution of atorvastatin calcium.
Organic solvent may be selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tetrahydrofuran, toluene or mixture(s) thereof.
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Atorvastatin calcium may be treated with aqueous ammonia solution at 0°C to 30°C for 30
minutes to 4 hours.
Aqueous ammonia solution may contain 25% weight / weight of ammonia gas.
A hazy solution of atorvastatin calcium may be filtered at 25°C through a ceiite bed to get a clear solution of atorvastatin calcium.
A clear solution of atorvastatin calcium may be concentrated at 25°C to 50°C under reduced pressure to obtain storage stable amorphous atorvastatin calcium.
Storage stable amorphous atorvastatin calcium obtained by the present invention may be dried at 40°C to 70°C under reduced pressure.
Storage stable amorphous atorvastatin calcium obtained by the present invention may contain 0.02% weight / weight to 0.1 % weight / weight of oxidative degradation impurities such as4-[6-(4-Fluoro-phenyl)-6-hydroxy-lb-isopropyl-6a-phenyl-la-phenylcarbamoyl-hexahydro-1, 2-dioxa-5a-aza-cyclopropa[a]inden-3-yl]-3-(R)-hydroxy-butyric acid; 4-(4-Fluoro-phenyl)-2, 4-dihydroxy-2-isopropyl-5-phenyl-3, 6-dioxa-bicyclo [3.1.0] hexane-1-carboxylic acid phenylamide and 4-[lb-(4~Fluoro-phenyl)-6-hydroxy-6-isopropyl-la-phenyl-6a-phenylcarbamoyl-hexahydro-l, 2-dioxa-5a-aza-cyclopropa[a]inden-3-yl]-3-(R)-hydroxy-butyric acid.
DESCRIPTION OF THE DRAWING
Figure 1 shows a Powder X-ray diffraction pattern of storage stable amorphous atorvastatin calcium.
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While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE
PREPARATION OF STORAGE STABLE AMORPHOUS ATORVASTATIN CALCIUM
Atorvastatin calcium (180 gm) is suspended in methanol (4.5 liters) containing aqueous
ammonia (45 ml) and stirred at 25 -30 °C for 1 hour. The resulting hazy solution is filtered
and the filtrate obtained is distilled off to afford solid atorvastatin calcium in amorphous
form. This amorphous atorvastatin calcium is dried at 55-60 C for 12 hours.
Yield: 165 gm
Purity: 99.90% (By HPLC)
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To
The Controller of Patents The patent Office, At Mumbai

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