AMORPHOUS ATORVASTATIN CALCIUM SALT

FIELD OF THE INVENTION

This invention in general relates to a process for preparing amorphous form of atorvastatin calcium. More specifically, but without restriction to the particular embodiments hereinafter described in accordance with the best mode of practice, this invention relates to a novel process for the preparation of amorphous atorvastatin calcium employing suitable solvent system.

BACKGROUND OF THE INVENTION

[R(R ^* ,R ^* )]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(l-methylethyl )-3-phenyl-4- [(phenylamino) carbonyl]-lH-pyrrole-l-heptanoic acid, commonly known as atorvastatin is known to be therapeutically useful compound. Atorvastatin calcium, a synthetic HMG-CoA reductase inhibitor, is used for the treatment of hyperlipidemia and hypercholesterolemia, both of which are risk factors for arteriosclerosis and coronary heart disease. For use in the treatment of aforementioned diseases, open dihydroxy carboxylic acid, lactone and various salt forms of atorvastatin have been synthesized.

US Patent No. 4,681,893 discloses certain trans-6-[2-(3- or 4-carboxamido substituted- pyrrol-l-yl)alkyl]-4-hydroxy-pyran-2-ones, which includes trans(+)-5-(4- fluorophenyl)-2-( 1 -methylethyl)-N,4-diphenyl- 1 -[2-(tetrahydro-4-hydroxy-6-oxo-2H- pyran-2-yl)ethyl]-lH-pyrrole-3-carboxamide, whereas US Patent No. 5,273,995 discloses that R-enantiomer of the ring-opened acid form of trans-5-(4-fluorophenyl)-2- (1 -methylethyl)-N,4-diphenyl- 1 -[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]- lH-pyrrole-3-carboxamide has surprising inhibition of the biosynthesis of cholesterol. Atorvastatin in its calcium salt form, i.e. [R(R ^* ,R ^* )]-2-(4-fluorophenyl)-β,δ-dihydroxy- 5-(l-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-lH-pyrrole-l-heptanoic acid calcium salt (2:1) having formula I; is more suited for developing formulations and has

I been recommended as a drag.

US Patent Nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,342,952 and 5,397,792 disclose various processes and key intermediates for preparing atorvastatin.

Atorvastatin calcium produced by the processes described in the above-mentioned US patents does not give amorphous form consistently but gives a mixture of crystalline and amorphous forms, which has unsuitable filtration and drying characteristics and are not suitable for large-scale production.

It is known that the amorphous forms in a number of pharmaceutical substances exhibit different dissolution characteristics and bioavailability patterns compared to crystalline forms (Konno T., Chem. Phar. Bull. 1990, 38, 2003-2007). For some therapeutic indications the bioavailability is one of the key parameters determining the form of the substance to be used in a pharmaceutical formulation. There is a constant need for processes which enable the preparation of atorvastatin in an amorphous form without simultaneous formation of crystalline form, or which will enable the conversion of the crystalline forms into the amorphous form.

Atorvastatin calcium is very slightly water-soluble, and it has been found that in comparison to amorphous form, crystalline forms are less readily soluble and adversely affect the bioavailability of atorvastatin in the body.

PCT International Application WO 97/03959 discloses novel crystalline forms of atorvastatin calcium designated as form I, form II and form IV and process for their preparation having more favorable filtration and drying characteristics. PCT application WO 97/03960 and US Patent No. 6,274,740 describe the processes for the preparation of amorphous form, by conversion of the crystalline form of atorvastatin. Process

isc ose t ere n comp ses sso v ng atorvastat n crysta ne orm n a non- hydroxylic solvent like tetrahydrofuran or mixtures of tetrahydrofuran and toluene. This process involves complete removal of the solvent under high temperature (about 9O ⁰ C) and high vacuum (about 5 mm) and 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 solvent at a manufacturing scale renders this process as less productive.

PCT International Application WO 00/71116 describes the process for the preparation of amorphous atorvastatin, which involves dissolving crystalline form in non- hydroxylated solvent followed by precipitation of amorphous atorvastatin by adding non-polar hydrocarbon solvent. In this case high levels of hydrocarbon are necessary to obtain the desired product. A similar approach is described in PCT International

Application WO 01/42209, which describes conversion of the crystalline form of atorvastatin to the amorphous form by dissolving in a variety of solvents including both non-hydroxylated solvents and lower alcohols, followed by precipitation with solvents in which atorvastatin is insoluble like non-polar hydrocarbons or aliphatic ethers. This process also is not recommended for commercial production of amorphous atorvastatin calcium due to the use of large excess of diethyl ether, which may not be safe on plant level.

PCT International Application WO 01/28999 describes the purification of crude amorphous atorvastatin calcium by dissolving qrude amorphous material in a large excess of boiling ethanol or 2-propanol and filtering the hot solution and recovering the material at low temperature.

Therefore, there is a need to provide a convenient and industrially scalable process for producing atorvastatin in amorphous form.

OBJECTS AND SUMMARY OF THE INVENTION

It is, therefore, an object of the present invention to improve upon limitations in the prior art. These and other objects are attained in accordance with the present invention

wherein there is provided several embodiments of a nove process for preparation of pure amorphous form of atorvastatin employing suitable solvent system.

In accordance with one preferred embodiment of the present invention, there is provided a process for preparation of amorphous atorvastatin calcium, wherein the process comprises the steps of;

(a) dissolving atorvastatin calcium in an organic solvent selected from the group comprising 1,4-dioxane, acetonitrile, toluene, anisole and t- butanol or a mixture thereof; (b) adding an anti-solvent into the solution prepared in step (a) selected from the group comprising cyclohexane, n-hexane, w-heptane, methyl t- butyl ether and methanol or a mixture thereof to get the precipitate; and (c) separating the resultant precipitate to obtain the amorphous atorvastatin calcium.

In accordance with another preferred embodiment of the present invention, there is provided a process for preparation of amorphous atorvastatin calcium, wherein the process comprises the steps of;

(a) preparing a solution of 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- phenylcarbamoyl-pyrrol-l-yl]-3,5-dihydroxy heptanoic acid t-butyl ester of formula (II) in lower alcohol,

II

(b) optionally preparing sodium salt;

(c) adding the aqueous solution of calcium salt to solution prepared in step (a) or optionally in step (b);

(d) removing the solvent and dissolving viscous residue in an organic solvent selected from the group comprising 1,4-dioxane, acetonitrile, toluene, anisole and t-butanol or a mixture thereof;

.

(e) adding an anti-solvent to the resultant solution prepared m the step (a) selected from the group comprising cyclohexane, /z-hexane, «-heptane, methyl r-butyl ether and methanol or a mixture thereof to get precipitate; and (f) separating the resultant precipitate to obtain amorphous atorvastatin calcium.

In accordance with yet another preferred embodiment of the present invention, there is provided a process for preparation of amorphous atorvastatin calcium, wherein the process comprises the steps of;

(a) preparing a solution of compound of formula (III) in a lower alcohol;

(b) optionally preparing sodium salt;

(c) adding the aqueous solution of calcium salt to solution prepared in step (a) or optionally in step (b) and cooling the same to obtain crude atorvastatin calcium;

(d) dissolving crude atorvastatin calcium obtained after step (c) in an organic solvent selected from the group comprising of 1,4-dioxane, acetonitrile, toluene, anisole and t-butanol or a mixture thereof;

(e) adding anti-solvent to the solution prepared in the step (d) selected from the group comprising of cyclohexane, /j-hexane, «-heptane, methyl t- butyl ether, and methanol or a mixture thereof to obtain the precipitate; and

(f) separating the resultant precipitate to obtain amorphous atorvastatin calcium.

In accordance with yet another embodiment of the present invention, there is provided a process for preparation of amorphous atorvastatin calcium, wherein amorphous atorvastatin is prepared by dissolving atorvastatin calcium in 1,4-dioxane at room temperature to moderate temperature and then slowly adding to the suitable anti-solvent

or mixture o suita e anti so vents un er stirring to o ain precipitate, wnicn are filtered and dried under vacuum.

In accordance with yet another embodiment of the present invention, there is provided a process for preparation of amorphous atorvastatin calcium, wherein amorphous atorvastatin is prepared by dissolving atorvastatin calcium in a mixture of ?-butanol and methanol at a moderate to high temperature and stirring at the same temperature for a period to obtain precipitate, which are filtered and dried under vacuum.

In accordance with still another embodiment of the present invention, there is provided a process for preparation of amorphous atorvastatin calcium, wherein amorphous atorvastatin is prepared by dissolving atorvastatin calcium in a mixture of acetonitrile and toluene at a moderate to high temperature, concentrated and then slowly added to the solution of ?-butyl methyl ether under stirring to obtain the precipitate, which are filtered and dried under vacuum.

In accordance with still another embodiment of the present invention, there is provided a process for preparation of amorphous atorvastatin calcium, wherein amorphous atorvastatin is prepared by dissolving atorvastatin calcium in a mixture of 1,4-dioxane and anisole at a moderate to high temperature, to which n-hexane is added to obtain the precipitate, which are filtered and dried under vacuum.

DETAILED DESCRIPTION OF THE INVENTION

The disclosed embodiment of the present invention deals with a process for the preparation of amorphous atorvastatin employing suitable solvent system.

The process for the preparation of the amorphous atorvastatin calcium using atorvastatin calcium can be in any form and the solvent used herein is specifically an organic solvent selected from 1,4-dioxane, acetonitrile, toluene, anisole and t-butanol alone or in different combinations and the anti-solvent used herein is selected from the group comprising cyclohexane, n-hexane, «-heptane, methyl t-butyl ether or methanol alone or in different combinations.

The process for the preparation of the amorphous atorvastatin calcium using a compound of formula (II) is disclosed in the present invention, wherein the process comprises dissolving a compound of formula (II) in lower alcohol at room temperature to moderate temperature, adding water and calcium hydroxide solution with stirring at 55-6O ⁰ C, cooling the reaction mixture, diluting with lower alcohol, filtering the solution to remove unreacted calcium hydroxide, concentrating the filtrate to get viscous residue, further dissolving the residue in dioxane at room temperature to moderate temperature, removing insoluble impurities by filtration, slowly adding the solution to the mixture of cyclohexane and methyl ϊ-butyl ether to obtain the precipitate, filtering the precipitate and drying under vacuum. The compound of formula (II) used in the process is prepared by the same procedure as mentioned in the prior art. Amorphous atorvastatin calcium is also be obtained by preparing the sodium salt from the compound of formula II and then converted into calcium salt followed by the procedure given above.

The process for the preparation of the amorphous atorvastatin calcium using a compound of formula (III) is disclosed in the present invention, wherein the process comprises dissolving a compound of formula (III) in lower alcohol at room temperature to moderate temperature and to which water and sodium hydroxide solution is added with stirring. Upon completion of hydrolysis water is added and then solution is washed with ethyl acetate and hexane twice. The solution is diluted with lower alcohol and calcium chloride solution is added to it at 6O ⁰ C with high agitation. Reaction mixture is cooled and then filtered to get precipitates of crude atorvastatin calcium. Crude atorvastatin calcium is further dissolved in dioxane at room temperature to moderate temperature and insoluble impurities are removed by filtration, and then solution is slowly added to the .mixture of cyclohexane and methyl t-butyl ether to get the precipitate. Precipitate is filtered and dried under vacuum. The compound of formula (III) used in the process is prepared by the same procedure as mentioned in the prior art. Amorphous atorvastatin calcium is also be obtained by preparing the sodium salt from the compound of formula III and then converted into calcium salt followed by the procedure given above.

The lower alcohol used in the process is selected from the group comprising methanol, ethanol, isopropyl alcohol etc., preferably, methanol.

Having thus described the various methods for the preparation of amorphous form of atorvastatin calcium of the present invention, the following examples are provided to illustrate specific embodiments of the present invention. They are, however, not intended to be limiting the scope of present invention in any way.

Example 1

Atorvastatin calcium (3.0 g) was dissolved in 1,4-dioxane (9.0 ml) by stirring at 45- 50 ⁰ C. The clear solution so obtained was slowly added to a mixture of cyclohexane and methyl r-butyl ether (150 ml) to get precipitate. The precipitated material was stirred at the same temperature. The product was filtered under suction and dried under vacuum in oven for 48 hrs.

Example 2 Atorvastatin calcium (5.0 g) was dissolved in 1,4-dioxane (50.0 ml) at 45-50 ⁰ C. The clear solution so obtained was slowly added to cyclohexane (500 ml) to get precipitate. The precipitated material was stirred at the same temperature. The product was filtered under suction and dried under vacuum in oven for 48 hrs.

Example 3

Atorvastatin calcium (1.0 g) was dissolved in 1,4-dioxane (10.0 ml) at 45-50 ⁰ C. The clear solution so obtained was added to «-heptane (100 ml) to get precipitate. The precipitated material was stirred at the same temperature. The product was filtered under suction and dried under vacuum in oven at for 15 hrs.

Example 4

Atorvastatin calcium (1.0 g) was dissolved in 1,4-dioxane (10.0 mil) at 45-50 ⁰ C. The clear solution so obtained was added to methyl t-butyl ether (100 ml) to get precipitate. The precipitated material was stirred at the same temperature. The product was filtered under suction and dried under vacuum in oven for 15 hrs.

Example 5

Atorvastatin calcium (3.0 g) was dissolved in 1,4-dioxane (9.0 ml) at 45-50 ⁰ C. The clear solution so obtained was added to diisopropyl ether (150 ml) to get precipitate.

.

The precipitated mateπal was stirred at the same temperature. The product was tiltered under suction and dried under vacuum in oven for 48 hrs.

Example 6 Atorvastatin calcium (1.0 g) was dissolved in a mixture of t-butanol (150 ml) and methanol (40 ml) at 80-85 ⁰ C. After the material was dissolved, the clear solution so obtained was stirred. The recrystallized product was filtered under suction and dried under vacuum in oven for 15 hrs.

Example 7

Atorvastatin Calcium (3.0 g) was dissolved in a mixture of acetonitrile (150 ml) and toluene (150 ml) at 70-75 ⁰ C. After the material was dissolved, the solution was concentrated. This clear concentrated solution so obtained was slowly added to methyl t-butyl ether (150 ml) to get precipitate. The precipitated material was stirred at the same temperature. The product was filtered under suction and dried under vacuum in oven for 48 hrs.

Example 8

Atorvastatin Calcium (0.5 g) was dissolved in a mixture of preheated 1,4-dioxane (5 ml) and anisole (45 ml) at 50-55 ⁰ C. The clear solution was cooled to 25-3O ⁰ C, and then n-hexane (100 ml) was added. The precipitated material was stirred. Filtered the material and dried under vacuum for 15 hr.

.- Example 9 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl -pyrrol-l-yl]-3,5- dihydroxy hep.tanoic acid /-butyl ester II (1.0 g) was dissolved in methanol (15 ml). After the compound was dissolved, water (1.0 ml), calcium hydroxide (0.28 g) were added to it and diluted with 25 ml of methanol, filtered the reaction mass to eliminate the unreacted calcium hydroxide. The solvent was removed to get a viscous residue, which was further dissolved in dioxane (5.0 ml) at 40-45 ⁰ C and removed the undissolved material by filtration. The clear filtrate was then added to a mixture of cyclohexane & methyl t-butyl ether (50 ml) to get precipitate. The precipitated material was further stirred at room temperature. Filtered the material and dried for 2 hrs in oven.

Example 10

7-[2-(4-fluorophenyl)-5-isopropylr3-phenyl-4-phenylcarbam oyl-pyrrol-l-yl]-3,5- dihydroxy heptanoic acid /-butyl ester II (5.0 g) was dissolved in 50ml of methanol followed by the addition of water (10ml). NaOH (0.8g) was added with stirring and monitored by HPLC. After the completion of hydrolysis, water (50 rnl) was added, and then aqueous layer was washed with 1 :1 mixture of ethyl acetate and cyclohexane. CaCl ₂ .2H ₂ O (0.98 g) in water (50 ml) was added to the reaction mixture at 55-6O ⁰ C. After complete addition, reaction mixture was cooled and filtered. Material was dried at 50-55 ⁰ C in vacuum oven to give crude atorvastatin calcium.

The above crude atorvastatin calcium was dissolved in dioxane (14.0 ml) at 40-45 ⁰ C. The clear filtrate was then slowly added to a mixture of cyclohexane & methyl ?-butyl ether (220 ml) to get precipitate. The precipitated material was stirred at room temperature, then filtered and dried to get amorphous atorvastatin calcium.

Example 11

Atorvastatin lactone III (5.0 g) was dissolved in 50ml of methanol followed by the addition of water (10ml). NaOH (0.8g) was added with stirring and monitored by HPLC. After the completion of hydrolysis, water (50 ml) was added, and then aqueous layer was washed with 1:1 mixture of ethyl acetate and cyclohexane. CaCl ₂ .2H ₂ O (0.98 g) in water (50 ml) was slowly added to the reaction mixture at 55-6O ⁰ C. After complete addition, reaction mixture was cooled and filtered. Material was dried at 50- 55 ⁰ C in vacuum oven to give crude atorvastatin calcium. The above crude atorvastatin calcium was dissolved in dioxane (10.5 ml) at 40-45 ⁰ C. The clear filtrate was then slowly added to a mixture of cyclohexane & methyl t-butyl ether (175 ml) to get precipitate. The precipitated material was stirred at roora _^ temperature, then filtered and dried to get amorphous atorvastatin calcium.

Certain modifications and improvements of the disclosed invention will occur to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims.