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THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION
(See section 10; rule 13)
TITLE OF INVENTION
PROCESS FOR PREPARATION OF AMORPHOUS ATORVASTATIN CALCIUM
LUPIN LIMITED
159, C.S.T. Road, Kalina, Santacruz (East)
Mumbai - 400 098, State of Maharashtra, India
an Indian Company
The following specification particularly describes the nature of this invention and the manner in which it is to be performed


PROCESS FOR PREPARATION OF AMOPRPHOUS ATORVASTATIN CALCIUM
FIELD OF THE INVENTION
The present invention relates to a novel process for preparation of amorphous atorvastatin calcium.
BACKGROUND OF THE INVENTION
Atorvastatin, chemically known as [R-(R*, R*)]-2-(4-fluorophenyl)-p, 8-dihydroxy-5- (1-methylethy))-3-phenyl-4- [(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid is an HMG-CoA reductase inhibitor and is used as an antihypercholesterolemic agent. Atorvastatin is marketed as the hemi-calcium salt trihydrate under the brand name LIPITOR.
Atorvastatin was first claimed and disclosed in US Patent No. 4,681,893, as the racemic lactone, i.e., trans-5- (4-fluorophenyl)-2-(1-methylethyl)-N, 4-diphenyl-1- [2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl]-1 H-pyrrole-carboxamide. The patent teaches a method of synthesizing the racemic atorvastatin lactone and sodium salt of (R*, R*)-2-(4-fluorophenyl)-p,8-dihydroxy-5- (1-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid ("racemic atorvastatin sodium") by treating the racemic lactone with sodium hydroxide in mixture of THF and water.
Atorvastatin, the pure [R(R*,R*)] enantiomer of 2-(4-fluorophenyl)-p, 8-dihydroxy-5- (1-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid and its hemi-calcium salt of formula (I) were first disclosed in US patent No. 5,273,995.


(I)

The US Patent 5,273,995 teaches a method of making the calcium salt of atorvastatin by first treating the atorvastatin lactone with sodium hydroxide in a mixture of methanol and water to get the sodium salt and treating the sodium salt with slight excess of CaCI2.2H20. Atorvastatin calcium thus obtained was further purified by recrystallization from a 5:3 mixture of ethyl acetate and hexane. However, there is no disclosure concerning the crystalline form of the hemi-calcium salt of atorvastatin in US Patent No. 5,273,995.
Atorvastatin calcium marketed as crystalline Form I trihydrate is covered in US Patent No. 5,969,156. The patent also covers two more crystalline forms, namely, Form II and Form IV. US Patent No. 6,121,461 claims and discloses crystalline atorvastatin calcium of form III, and crystalline atorvastatin calcium Form V is disclosed in PCT publication No. WO 01/36384 (PCT Application No. PCT/US00/31555).
Processes for preparing atorvastatin salts, atorvastatin lactone, and key intermediates are disclosed in US Patent Nos. 6,777,552; 6,528,661; 5,298,627; 5,003,080; 5,097,045; 5,124,482; 5,149,837; 5,216,174; 5245,047; 5,280,126; and Baumann, K.I, et al. Tetrahedron Letters, 33, 2283-2284, (1992).
Atorvastatin calcium is very slightly water-soluble, and it has been found that the crystalline forms are less readily soluble than the amorphous form, which may cause problems in the bioavailability of atorvastatin in the body. The processes disclosed in the

above mentioned process patents does not give amorphous atorvastatin that has good
filterability and stability that are essentially required for large-scale production.
There have been processes developed for converting crystalline forms of atorvastatin to
amorphous form.
The following documents disclose methods for making atorvastatin calcium in
amorphous form.
US Patent No. 6,087,511 claims and discloses a process for the preparation of amorphous atorvastatin calcium by dissolving crystalline Form I atorvastatin calcium in a non-hydroxylic solvent selected from a group consisting of tetrahydrofuran, and mixtures of tetrahydrofuran and toluene. According to the enabling disclosure, crystalline Form I is dissolved in an approximately four-fold amount of a 3:2 mixture of tetrahydrofuran and toluene, whereupon the solvent is removed by first at 35°C, and thereupon at 85°C, under vacuum at 6-8mm of Hg for 4 days.
The disadvantages of the process are the use of non-nature friendly solvent and the product still contains solvent residues even after drying under high vacuum at elevated temperature.
US Patent No. 6,613,916 teaches a method for preparing atorvastatin calcium in an amorphous form by precipitating atorvastatin using a solvent of second type such as ether from a solution of atorvastatin, which is provided, with a solvent of first type selected from methanol, ethanol, or acetone.
The method is disadvantageous in that it uses a minimum of 10 times the volume of solvent to prepare the atorvastatin solution and 5 times the volume of solvent of second type to precipitate.
The process claimed and disclosed for the preparation of amorphous atorvastatin calcium in US Patent No. 6,528,660 comprises dissolving the crystalline form of atorvastatin calcium in a non-hydroxylic solvent such as tetrahydrofuran and reprecipitating amorphous atorvastatin either by adding a non polar organic solvent, or adding the solution of atorvastatin calcium to non polar organic solvents selected from cyclohexane or n-hexane or n-heptane. The method uses large amount of solvent and solvent residue in the product obtained was up to 0.6%.

PCT publication No. WO 03/099785 A1 claims and discloses a method for making the amorphous atorvastatin calcium by dissolving a mixture of crystalline and amorphous atorvastatin calcium in a solvent consisting of an acyclic ketone such as acetone, 2-butanone, 3-pentanone, 3-pentanone or 2-hexanone, filtering the solution and removing the solvent under vacuum at 40 to 50°C.
PCT publication No. WO 03/018547 A2 claims and discloses a method for making the amorphous atorvastatin calcium by precipitating from a solution of atorvastatin calcium in halogenated aliphatic hydrocarbons such as methylene chloride, ethylene dichloride, chloroform, with a anti-solvent selected from diisopropyl ether, diethyl ether, or a non-polar hydrocarbon like petroleum ether.
US Patent Application Publication No. 2004/0063969 A1 claims and discloses a process for making amorphous atorvastatin calcium by dissolving crude atorvastatin calcium in a alkanol containing 2-4 carbon atoms or a mixture of two or more such alkanols under heating at the boiling point of the alkanol and isolating the amorphous atorvastatin calcium precipitated after cooling. The preferred alkanols are isopropanol or ethanol. According to the enabling disclosures in Example 1 and Example 2, the method uses a large excess of alkanol used in an amount of 40 to 50 ml per 1.0 g of crude atorvastatin.
US Patent Application Publication No. 2003/0212279 A1 discloses a method of preparing amorphous atorvastatin calcium from any of the crystalline form of atorvastatin calcium by refluxing in acetone for 16 hrs, or by sonicating in acetonitrile for a few minutes or by ball milling.

On scrutiny of the prior art methods it is revealed that the prior art methods for preparing amorphous atorvastatin calcium, suffer from one or more of the following disadvantages, i) use of solvents of toxic potential that are frowned upon by the ICH guidelines, ii) very large ratio of substance to solvent, iii) formation of jelly type material not having good filterability, iv) necessity of drying at higher temperature for long hours leading to the
formation of lactone impurities above the acceptable limits, v) solvent residues higher than acceptable limit,
These disadvantages adversely affect the quality of the product and make the process not suitable for large-scale production. For example, the method disclosed in the product patent US 5,273,995 to purify atorvastatin calcium by crystallizing from a solution of ethyl acetate by adding n-hexane lead to the formation of a jelly type material that required tedious filtration process and requiring long hours of drying under vacuum at a temperature about 40 to 50°C. Further, it was observed that the formation of lactone impurity would increase to unacceptable limit (>0.5%) with increase in drying time. Hence there is a need for practical synthesis of amorphous atorvastatin calcium.
OBJECT OF THE INVENTION
It is an object of the present invention to provide an efficient process for the production of amorphous atorvastatin calcium, which eliminates the deficiencies of prior art methods and is convenient to operate on large-scale production.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for the production of amorphous atorvastatin calcium, that comprises, providing a solution of atorvastatin calcium in a solvent selected from halogenated aliphatic hydrocarbon, dimethyl formamide, dimethyl acetamide or a lower alkyl organic acid; adding the atorvastatin calcium solution to an anti-solvent selected from tert-butyl alcohol, n-butyl alcohol, acetonitrile, or esters such as /so-propyl acetae or tert-butyl acetate; concentrating the resulting solution to precipitate the atorvastatin calcium.

The process of the present invention has the following advantages,
i) there is no jelly type formation of atorvastatin calcium during precipitation,
ii) superior filterability,
iii) fast drying characteristics of the product
iv) lactone impurity level is less than 0.1%,
v) easy to operate on large scale,
vi) formation of amorphous atorvastatin calcium of suitable bulk density.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of amorphous atorvastatin calcium, which comprises:
a) providing a solution of atorvastatin calcium of formula (I) in a solvent selected from halogenated aliphatic hydrocarbon, dimethyl formamide, dimethyl acetamide or a lower alkyl organic acid,
b) adding an anti-solvent or adding the solution of atorvastatin calcium to anti-solvent selected from tert-butyl alcohol, iso-butyl alcohol, n-butyl alcohol, acetonitrile,iso-propyl acetate, /'so-butyl acetate or tert-butyl acetate,
c) concentrating the solution obtained in step (b) to precipitate atorvastatin calcium,
d) separating the precipitate formed in step (c) from the solvent mixture.
The present invention is described in more details by referring to the following
embodiments.
According to the process of present invention, the solution of atorvastatin calcium may
be obtained from the last step of the synthesis of atorvastatin calcium described in
scheme 1, or by dissolving the atorvastatin calcium obtained by prior art methods in a
solvent.

Scheme 1
The solvent for providing the solution of atorvastatin calcium is selected from halogenated aliphatic hydrocarbon, for example, dichloromethane, chloroform, 1,2-dichloroethane and the like, dimethyl formamide, dimethyl acetamide, or lower alkyl organic acids such as acetic acid. Particularly preferred solvents consisting of dichloromethane, chloroform and 1,2-dichloroethane, which can be easily removed in the drying and the atorvastatin calcium has good solubility in these solvents.
The atorvastatin calcium is precipitated from its solution either by adding an anti-solvent or by adding the solution of atorvastatin calcium to an anti-solvent. The anti-solvent used in the process of the present invention is selected from the group of solvents, in which atorvastatin is insoluble or very slightly soluble. Preferred anti-solvents are terf-butyl alcohol, iso-butyl alcohol, n-butyl alcohol, acetonitrile, iso-propyl acetate, iso-butyl acetate or terf-butyl acetate. Particularly preferred solvents are terf-butyl alcohol, terf-butyl acetate, and acetonitrile.
According to a preferred embodiment, amorphous atorvastatin calcium is obtained by adding the solution of atorvastatin calcium to 1-3 times the volume of the

anti-solvent, concentrating the resulting solution to bring a supersaturated state by distilling out the solvent to 10 to 15% of volume with respect to anti-solvent.
The amorphous atorvastatin calcium is recovered by filtration at ambient temperature. Filtered material, a semi-dry powder, is further dried under vacuum to afford amorphous material. Preferably, the material is dried under vacuum at about 20 to 80°C for 6 to 24 hrs. Most preferably, drying is carried out at about 50 to 55°C.
Amorphous atorvastatin calcium prepared according to the process of the present invention may be characterized by its X-ray powder diffraction pattern as shown in Fig.1. X-ray powder diffraction shows no peaks thus demonstrating the amorphous nature of the product.
The invention is further illustrated by the following non-limiting examples.
EXAMPLE 1
To a solution of compound II (25 g) in methanol (250 ml) was added 3N hydrochloric acid (79.5 ml) at 25 to 30°C and stirred at 35 to 40°C for 3 to 4 hrs. Aqueous NaOH (15 g in 125 ml of water) solution was added at 25 to 30°C and the reaction mixture was warmed to 35 to 40°C for 3 to 4 hrs to get the atorvastatin sodium salt. The pH of the solution was adjusted to 7-7.5 by adding ~3N hydrochloric acid (79.5 ml). A solution of Ca(OAc)2 (3.6 g) in water (25 ml) was added at 40 to 45°C, cooled to 25 to 30°C and stirred for 2 hrs. The resulted slurry was extracted into dichloromethane (125 ml); the dichloromethane layer was poured into tert-butyl alcohol (250 ml). The dichloromethane was removed by distillation at ~30°C under vacuum to obtain a slurry that was stirred at 25 to 30°C for 1 hr, filtered and dried at 50 to 55°C under vacuum for 24 hrs; yield: 20 g. X-ray powder diffraction pattern demonstrates the amorphous nature of the product.
EXAMPLE 2
Atorvastatin calcium (25 g) was dissolved in dichloromethane (125 ml) at 30 to 35°C. The solution obtained was poured into tert-butyl alcohol (250 ml) and dichloromethane was distilled out at ~30°C under reduced pressure. The slurry obtained was stirred for 1 hr at 25 to 30°C, filtered and dried at 50 to 55°C under vacuum for 24 hrs; yield: 19 g. The properties analyzed match with the properties of the product of example 1.

EXAMPLE 3
To a solution of compound II (25 g) in methanol (250 ml) was added 3N hydrochloric acid (79.5 ml) at 25 to 30°C and stirred at 35 to 40°C for 3 to 4 hrs. Aqueous NaOH (15 g in 125 ml of water) solution was added at 25 to 30°C and the reaction mixture was warmed to 35 to 40°C for 3 to 4 hrs to get the atorvastatin sodium salt. The pH of the solution was adjusted to 7-7.5 by adding -3N hydrochloric acid (79.5 ml). A solution of Ca(OAc)2 (3.6 g) in water (25 ml) was added at 40 to 45°C, cooled to 25 to 30°C and stirred for 2 hrs. The resulted slurry was extracted into dichloromethane (125 ml); the dichloromethane layer was poured into terl-butyl acetate (250 ml). The dichloromethane was removed by distillation at -30°C under vacuum to obtain a slurry that was stirred at 25 to 30°C for 1 hr, filtered and dried at 50 to 55°C under vacuum for 24 hrs; yield: 22 g. The properties analyzed match with the properties of the product of example 1.
EXAMPLE 4
Atorvastatin calcium (25 g) was dissolved in dichloromethane (125 ml) at 30 to 35°C. The solution obtained was poured into terl-butyl acetate (250 ml) and dichloromethane was distilled out at ~30°C under reduced pressure. The slurry obtained was stirred for 1 hr at 25 to 30°C, filtered and dried at 50 to 55°C under vacuum for 24 hrs; Yield: 22 g. The properties analyzed match with the properties of the product of example 1.

We claim:
A process for the preparation of amorphous atorvastatin calcium, which comprises:
a) providing a solution of atorvastatin calcium in a solvent selected from the group consisting of halogenated aliphatic hydrocarbon, dimethyl formamide, dimethyl acetamide, acetic acid;
b) adding an anti-solvent or adding the solution of atorvastatin calcium to the anti-solvent,
c) concentrating the solution obtained in step (b) to precipitate atorvastatin calcium,
d) separating the precipitate formed in step (c) from the solvent mixture.
A process according to claim 1, wherein the halogenated aliphatic hydrocarbon, is dichloromethane, chloroform or 1,2-dichloroethane.
A process according to claim 1 wherein the anti-solvent is selected from tert-butyl alcohol, tert-butyl acetate or acetonitrile.
A process according to claim 1 wherein the anti-solvent is tert-butyl alcohol.
A process according to claim 1 wherein the halogenated aliphatic hydrocarbon is dichloromethane and anti-solvent is tert-butyl alcohol.
A process according to claim 1 wherein the halogenated aliphatic hydrocarbon is dichloromethane and anti-solvent is tert-butyl acetate.
A process according to claim 1 wherein the solution of atorvastatin calcium is provided during the course of the synthesis of atorvastatin calcium.

A process according to claim 1 wherein the solution of atorvastatin calcium is provided by dissolving atorvastatin calcium in a solvent.
Dated this 14th day of October 2004

S. MAJUMDAR
Of S. MAJUMDAR & CO.
Applicants' Agent