WO2008129562A2 - An improved process for the preparation of stable amorphous atorvastatin hemi calcium and their salts thereof - Google Patents

An improved process for the preparation of stable amorphous atorvastatin hemi calcium and their salts thereof Download PDF

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WO2008129562A2
WO2008129562A2 PCT/IN2008/000249 IN2008000249W WO2008129562A2 WO 2008129562 A2 WO2008129562 A2 WO 2008129562A2 IN 2008000249 W IN2008000249 W IN 2008000249W WO 2008129562 A2 WO2008129562 A2 WO 2008129562A2
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mixture
product
aliphatic
addition
solvent
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PCT/IN2008/000249
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French (fr)
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WO2008129562A3 (en
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Sanjay Suri
Tapan Kashyap
Madan Pal Tanwar
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Morepen Laboratories Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to an improved process for the preparation of stable amorphous atorvastatin hemi calcium and their salts .It also relates to a stable pure amorphous atorvastatin calcium and a process thereof.
  • Atorvastatin calcium salt of formula (I) chemically hemicalcium salt of [R-(R*,R*)]-2-(4- fluorophenyl)- ⁇ , ⁇ -dihydroxy-5-(l-methylethyl)-3-phenyl-4-(phenylcarbamoyl)-lH-pyrrole-l- heptanoic acid is marketed under the brand name LipitorTM. It has the structure as given below:
  • Atorvastatin hemi calcium salt is a reductase inhibitor of the enzyme 3-hydroxy-3- methylglutarate-coenzyme A (HMG-CoA) and therefore is a useful anti hyperlipoproteinemic agent. It has proven to be a highly effective medicament for the treatment of disorders such as hyperlipidemia and hypercholesterolemia which are the known risk factors for arteriosclerosis and coronary heart disease.
  • US patent 5,273,995 reported the inhibition of the biosynthesis of cholesterol by the R isomer of Atorvastatin hemi calcium salt
  • US patent 5,969,156 discloses novel crystalline forms of Atorvastatin hemi calcium salt of formula (I) and their preparation.
  • a procedure for the conversion of crystalline form to the amorphous form of Atorvastatin hemi calcium salt of formula (I) has been reported in US patent 6,274,740B 1.
  • Atorvastatin hemi calcium salt of formula (I) can be prepared by various methods described in the above mentioned patents but the product obtained is not of high purity.
  • the present invention provides to stable pure amorphous atorvastatin calcium and a process therefore.
  • the invention provides methods for the purification of crude atorvastatin hemi calcium salt and preparation of amorphous Atorvastatin hemi calcium salt of formula (I) using different solvent mixtures in variable ratios in the presence of antioxidant and an amine. It resulted in the increased purity of Atorvastatin hemi calcium salt of formula (I) in amorphous form. This ultimately will result in the better stability of the product.
  • amorphous Atorvastatin hemi calcium salt of formula (I) which comprises, a) hydrolyzing 1,3-dioxane ring of compound of formula (II) by aq. hydrochloric acid in methanol. b) in situ hydrolysis of tert-butyl group with sodium hydroxide to form Atorvastatin sodium salt solution followed by its washing with a mixture of ethyl acetate-hexane. c) addition of a single or a mixture of two or more antioxidants and or optionally in presence of an amine. d) addition of the Atorvastatin sodium salt solution to an aqueous calcium chloride or calcium acetate solution.
  • Fig 1 shows the synthetic route of amorphous Atorvastatin calcium salt of formula (I).
  • the main aspect of this invention is to provide amorphous Atorvastatin calcium salt of high purity i.e. almost impurity free product.
  • amorphous Atorvastatin hemi calcium salt of formula (I) which comprises, a) hydrolyzing 1,3-dioxane ring of compound of formula (II) by aq. hydrochloric acid in methanol. b) in situ hydrolysis of tert-butyl group with sodium hydroxide to form Atorvastatin sodium salt solution followed by its washing with a mixture of ethyl acetate-hexane. c) addition of a single or a mixture of two or more antioxidants and or optionally in presence of an amine. d) addition of the Atorvastatin sodium salt solution to an aqueous calcium chloride or calcium acetate solution.
  • step (i) optionally seeding with amorphous atorvastatin calcium.
  • step (i) optionally seeding with amorphous atorvastatin calcium.
  • step (i) filtering the slurry to get wet cake.
  • step (h) washing of wet cake by stirring in a binary, ternary or quaternary mixture of aliphatic alcohol, aliphatic ether, aliphatic nitrile, halogenated aliphatic hydrocarbon and water using antioxidant.
  • h) filtering the product and optionally drying under vacuum.
  • i) dissolving the wet product of step (h) in single organic solvent or a mixture of two or more organic solvents followed by addition of antioxidant and optionally concentrating the solution by recovery of solvent, j) addition of mass of step (i) to an anti - solvent or addition of an anti-solvent to the mass of step (i).
  • k) filtering and drying the product by conventional methods to afford amorphous
  • the invention provides a purification process for the preparation of stable amorphous Atorvastatin calcium salt of formula (I) which comprises;
  • Atorvastatin calcium of formula (I) by stirring in a binary, ternary or quaternary mixture of aliphatic alcohol, aliphatic ether, aliphatic nitrile, halogenated aliphatic hydrocarbon and water using antioxidant.
  • II. filtering the product and optionally drying under vacuum.
  • III. dissolving the wet product of step (II) in single organic solvent or a mixture of two or more organic solvents followed by addition of antioxidant and optionally concentrating the solution by recovery of solvent.
  • the organic amines used in step (c) are amines like N, N-diisopropylethylamine, tert-butyl amine, triethyl amine, N-methyl glucamine etc.
  • the antioxidant used in step (c), (g), (i), I and III are taken from butylated hydroxyl toluene, butylated hydroxyl anisole, t-butyl hydroquinone, hydroquinone monomethyl ether or some sulphur compounds like l-(merca ⁇ tomethyl) cyclopropane acetic acid, its methyl ester, thiophenol and compounds like chromophore EL etc. It may be pertinent to mention here that employing antioxidant optionally with amine in step (c), (g), & I is new. The use of sulphur compounds as antioxidant in all steps is a new concept.
  • the aliphatic alcohols are selected from Ci -C 4 aliphatic alcohols preferably methanol, ethanol, propanol, butanol or a mixture thereof;
  • the aliphatic ethers are selected from tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, tert-butyl methyl ether or a mixture thereof.
  • Halogenated aliphatic hydrocarbons are selected from methylene chloride, chloroform, carbon tetrachloride or their mixture.
  • the ratio of various solvents in the binary mixture used in step (g) & I is taken as 1-20 : 20-1.
  • the ratio of various solvents in the ternary mixture used in step (g) & I is taken as 1-20: 1-20: 1-20.
  • the ratio of various solvents in the quaternary mixture used in step (g) & I is taken as 1-15: 1-15: 1-15: 1-15.
  • the temperature in step (g) & I for washing of Atorvastatin hemi calcium salt of formula (I) 5 is ranging from O 0 C to 100 0 C.
  • the organic solvents used for dissolution of product in step (i) are selected from aliphatic esters like ethyl acetate, propyl acetate, butyl acetate; aliphatic nitrites like acetonitrile, propionitrile; chlorinated hydrocarbons like methylene chloride, chloroform, carbon tetrachloride or a mixture of two or more above mentioned solvents.
  • the anti-solvent used for crystallization of the final product in step (j) & IV are selected from C4-C8 aliphatic long or branched chain hydrocarbons like butane, pentane, hexane, heptane, octane ; aliphatic ethers like diisopropyl ether, t- butylmethyl ether or a mixture of two or more of these solvents. Water can be used as anti- solvent for the crystallization of final product.
  • the drying temperature of product in step (k) & V is ranging from 2O 0 C to 100 0 C.
  • step (g) & I the washing of crude or impure atorvastatin hemi calcium salt using binary, ternary or quaternary mixtures of organic solvents in step (g) & I resulted in the increase in purity from 98.0% to 99.90% i.e. almost impurity free product is obtained.
  • the solvent is removed at reduced pressure to reduce the volume to one third and a mixture of methanol (l.Oltr) and water (3.01tr) is added and stirred for 30 minutes.
  • a mixture of n-hexane (l.Oltr), ethyl acetate (l.Oltr) is added, stirred for 15 minutes and aq. layer is separated.
  • the pH of aq. layer is adjusted to 8.0-8.5 and stirred for 30 minutes at 40-45 0 C. To this an aq.
  • the concentrated organic layer is added dropwise into precooled diisopropyl ether (2.5ltr) at 10- 15°C under stirring in 45minutes (Alternatively diisopropyl ether can be added to the concentrated methylene chloride layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-50 0 C in a vacuum dryer for 24-48hr and 65g atorvastatin hemi calcium salt in amorphous form was obtained. HPLC purity : 99.92%; Assay (OAB, HPLC) : 99.80%
  • the concentrated organic layer is added dropwise into precooled diisopropyl ether (2.51tr) at
  • the concentrated organic layer is added drop wise into pre cooled diisopropyl ether (2.51tr) at 10-15 0 C under stirring in 45minutes (Alternatively diisopropyl ether can be added to the concentrated methylene chloride layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-50 0 C in a vacuum dryer for 24-48hr and 56g atorvastatin hemi calcium salt in amorphous form was obtained. HPLC purity: 99.80%; Assay (OAB, HPLC): 99.65%
  • Atorvastatin hemi calcium salt (10Og) is added followed by addition of butylated hydroxy anisole (0.5Og) and the reaction mixture is stirred at 40-45 0 C for 2-3hr.
  • the product is filtered and washed with a mixture of ter-butanol - acetonitrile - water (50ml:40ml:175mI).
  • the resulting solid mass is dissolved in methylene chloride (2.0Itr) at 25-35°C and aq. layer is separated and butylated hydroxy anisole (0.50g) is added to the organic layer. Then organic layer is concentrated up to about 800ml. at 40-42 0 C at atmospheric pressure.
  • the concentrated organic layer is added drop wise into pre cooled diisopropyl ether (2.51tr) at 10-15 0 C under stirring in 45minutes (Alternatively diisopropyl ether can be added to the concentrated methylene chloride layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-50 0 C in a vacuum dryer for 24-48hr and 5Og of atorvastatin hemi calcium salt in amorphous form was obtained. HPLC purity: 99.75%; Assay (OAB, HPLC): 99.60%
  • the resulting solid mass is dissolved in a mixture of acetonitrile (0.5ltr) and methylene chloride (2.01tr) at 25-35 0 C and butylated hydroxy anisole (0.50g) is added to the organic layer. Then organic layer is concentrated up to about 800ml. at 40-50 0 C at atmospheric pressure. The concentrated organic layer is added dropwise into precooled diisopropyl ether (2.51tr) at 10- 15 0 C under stirring in 45minutes (Alternatively diisopropyl ether can be added to the concentrated methylene chloride layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-50 0 C in a vacuum dryer for 24-48hr and 6Og atorvastatin calcium salt in amorphous form was obtained.
  • the resulting solid mass is dissolved in a mixture of ethylacetate (3.01tr) & methanol (l.Oltr) at 25-35°C and butylated hydroxy anisole (0.5Og) is added to it.
  • organic layer is concentrated up to about 800ml. at 40-50°C at reduced pressure.
  • the concentrated organic layer is added dropwise into precooled n-hexane (2.51tr) at 10-15 0 C under stirring in 45minutes (Alternatively n-hexane can be added to the concentrated organic layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature.
  • the concentrated organic layer is added dropwise into pre cooled n-heptane (2.51tr) at 10-15 0 C under stirring in 45minutes (Alternatively n-heptane can be added to the concentrated ethyl acetate layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-50 0 C in a vacuum dryer for 24-48hr and 50g of atorvastatin hemi calcium salt in amorphous form was obtained.
  • the concentrated organic layer is added dropwise into pre cooled DM water (2.51tr) at 10-15 0 C under stirring in 45minutes (Alternatively precooled DM water can be added to the concentrated organic layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-50 0 C in a vacuum dryer for 24-48hr and 6Og atorvastatin calcium salt in amorphous form was obtained. HPLC purity: 99.70%; Assay (OAB, HPLC): 99.40%
  • Atorvastatin calcium salt To a mixture of methanol - tetrahydrofuran - water (400ml:500ml:1.751tr) at 40-45 0 C, wet sample of crude Atorvastatin hemi calcium salt (10Og) is added followed by addition of t-butyl hydroquinone (0.50g) and the reaction mixture is stirred at 40-45 0 C for 2-3hr. The product is filtered and washed with a mixture of methanol - tetrahydrofuran - water (40ml:50ml: 175ml).
  • the resulting solid mass is dissolved in a mixture of acetonitrile (0.501tr) and methylene chloride (2.01tr) at 25-35 0 C and the solvent is removed at reduced pressure.
  • the resulting solid is further dried under vacuum at 40-45 0 C for 12-16hr to get the product.
  • the resulting solid mass is dissolved in toluene (2.01tr) at 25-35 0 C and aq. layer is separated and butylated hydroxy anisole (0.50g) is added to the toluene layer.
  • organic layer is concentrated up to about 800ml. at 50-60 0 C at reduced pressure.
  • the concentrated organic layer is added drop wise into pre cooled diisopropyl ether (2.51tr) at 10-15 0 C under stirring in 45minutes (Alternatively diisopropyl ether can be added to the concentrated methylene chloride layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature.

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Abstract

The present invention describes the preparation of highly pure (i.e. filling in ICH quality parameters with respect to related substances) stable amorphous Atorvastatin calcium salt comprising (a) hydrolysis of 1,3-dioxane ring of (4R-Cis)-1,1-dimethylethyl-6-[2-[2-(4- fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1lH-pyrrol-1-yl]ethyl]-2,2- dimethyl-1,3-dioxane-4-acetate having formula I, (b) in situ hydrolysis of t-butyl group to form Atorvastatin sodium salt solution (c) addition of a single or a mixture of two or more antioxidants and optionally an amine (d) addition of Atorvastatin sodium salt solution to an aqueous solution of calcium acetate or calcium chloride (e) optionally seeding with amorphous atorvastatin calcium (f) filtration and washing of obtained cake using different solvents mixtures in presence of antioxidants (g) dissolving above cake in a solvent or a mixture of two or more organic solvents followed by crystallization of product using an antisolvent.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF STABLE AMORPHOUS ATORVASTATIN HEMI CALCIUM AND THEIR SALTS THEREOF
The present invention relates to an improved process for the preparation of stable amorphous atorvastatin hemi calcium and their salts .It also relates to a stable pure amorphous atorvastatin calcium and a process thereof.
BACKGROUND OF THE INVENTION
Atorvastatin calcium salt of formula (I), chemically hemicalcium salt of [R-(R*,R*)]-2-(4- fluorophenyl)-β,δ-dihydroxy-5-(l-methylethyl)-3-phenyl-4-(phenylcarbamoyl)-lH-pyrrole-l- heptanoic acid is marketed under the brand name Lipitor™. It has the structure as given below:
Figure imgf000002_0001
(I)
Atorvastatin hemi calcium salt is a reductase inhibitor of the enzyme 3-hydroxy-3- methylglutarate-coenzyme A (HMG-CoA) and therefore is a useful anti hyperlipoproteinemic agent. It has proven to be a highly effective medicament for the treatment of disorders such as hyperlipidemia and hypercholesterolemia which are the known risk factors for arteriosclerosis and coronary heart disease.
Processes for the manufacture of Atorvastatin hemi calcium salt, formulations of atorvastatin and its key intermediates have been described in various patents including : United States Patent Numbers 4,681,893; 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; 5,273,995; 5,280,126; 5,298,627; 5,342,952; 5,397,792; 5,446,054; 5,470,981; 5,489,690; 5,489,691; 5,510,488; 5,686,104; 5,969,156; 5,998;633; 6,087,511; 6,121,461; 6,126,971; 6,433,213; 6,476,235; 6,528,660; 6,600,051 ; 6,605,759; 6,613,916; 6,646,133; 6,730,797; 6,867,306; 6,891,047; WO99/32434; WO01/36384; WO02/41834; WO02/43667; WO02/43732; WO02/051804; WO02/057228; WO02/057229; WO02/057274; WO02/059087; WO02/083637; WO02/083638; WO03/011826; WO03/050085; WO03/07072 and WO 04/022053.
US patent 5,273,995 reported the inhibition of the biosynthesis of cholesterol by the R isomer of Atorvastatin hemi calcium salt, whereas US patent 5,969,156 discloses novel crystalline forms of Atorvastatin hemi calcium salt of formula (I) and their preparation. A procedure for the conversion of crystalline form to the amorphous form of Atorvastatin hemi calcium salt of formula (I) has been reported in US patent 6,274,740B 1.
US patent 6,528,660Bl; US 6,613,916B2; US 6,646,133Bl; and WO 03/078379 described the production of amorphous Atorvastatin calcium.
Although Atorvastatin hemi calcium salt of formula (I) can be prepared by various methods described in the above mentioned patents but the product obtained is not of high purity.
Since purity of the product plays an important role in the stability of the product, therefore still an improved and efficient process is required for preparation and purification of compound of formula (I) which can be utilized in the scale-up of the product having appropriate yield along with high purity.
SUMMARY OF THE INVENTION
The present invention provides to stable pure amorphous atorvastatin calcium and a process therefore. Particularly, the invention provides methods for the purification of crude atorvastatin hemi calcium salt and preparation of amorphous Atorvastatin hemi calcium salt of formula (I) using different solvent mixtures in variable ratios in the presence of antioxidant and an amine. It resulted in the increased purity of Atorvastatin hemi calcium salt of formula (I) in amorphous form. This ultimately will result in the better stability of the product.
According to other aspect of the invention provides a purification process for the preparation of amorphous Atorvastatin hemi calcium salt of formula (I) which comprises, a) hydrolyzing 1,3-dioxane ring of compound of formula (II) by aq. hydrochloric acid in methanol. b) in situ hydrolysis of tert-butyl group with sodium hydroxide to form Atorvastatin sodium salt solution followed by its washing with a mixture of ethyl acetate-hexane. c) addition of a single or a mixture of two or more antioxidants and or optionally in presence of an amine. d) addition of the Atorvastatin sodium salt solution to an aqueous calcium chloride or calcium acetate solution. e) optionally seeding with amorphous atorvastatin calcium. f) filtering the slurry to get wet cake. g) washing of wet cake by stirring in a binary, ternary or quaternary mixture of aliphatic alcohol, aliphatic ether, aliphatic nitrile, halogenated aliphatic hydrocarbon and water using antioxidant. h) filtering the product and optionally drying under vacuum. i) dissolving the wet product of step (h) in single organic solvent or a mixture of two or more organic solvents followed by addition of antioxidant and optionally concentrating the solution by recovery of solvent. j) addition of mass of step (i) to an anti - solvent or addition of an anti-solvent to the mass of step (i). k) filtering and drying the product by conventional methods to afford amorphous Atorvastatin hemi calcium salt of formula (I) of high purity i.e. almost impurity free.
BRIEF DESCRIPTION OF THE FIGURES
Fig 1 shows the synthetic route of amorphous Atorvastatin calcium salt of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
The main aspect of this invention is to provide amorphous Atorvastatin calcium salt of high purity i.e. almost impurity free product.
According to other aspect of the invention provides a purification process for the preparation of amorphous Atorvastatin hemi calcium salt of formula (I) which comprises, a) hydrolyzing 1,3-dioxane ring of compound of formula (II) by aq. hydrochloric acid in methanol. b) in situ hydrolysis of tert-butyl group with sodium hydroxide to form Atorvastatin sodium salt solution followed by its washing with a mixture of ethyl acetate-hexane. c) addition of a single or a mixture of two or more antioxidants and or optionally in presence of an amine. d) addition of the Atorvastatin sodium salt solution to an aqueous calcium chloride or calcium acetate solution. e) optionally seeding with amorphous atorvastatin calcium. f) filtering the slurry to get wet cake. g) washing of wet cake by stirring in a binary, ternary or quaternary mixture of aliphatic alcohol, aliphatic ether, aliphatic nitrile, halogenated aliphatic hydrocarbon and water using antioxidant. h) filtering the product and optionally drying under vacuum. i) dissolving the wet product of step (h) in single organic solvent or a mixture of two or more organic solvents followed by addition of antioxidant and optionally concentrating the solution by recovery of solvent, j) addition of mass of step (i) to an anti - solvent or addition of an anti-solvent to the mass of step (i). k) filtering and drying the product by conventional methods to afford amorphous
Atorvastatin hemi calcium salt of formula (I) of high purity i.e. almost impurity free.
Alternatively, the invention provides a purification process for the preparation of stable amorphous Atorvastatin calcium salt of formula (I) which comprises;
I. washing of crystalline or amorphous Atorvastatin calcium of formula (I) by stirring in a binary, ternary or quaternary mixture of aliphatic alcohol, aliphatic ether, aliphatic nitrile, halogenated aliphatic hydrocarbon and water using antioxidant. II. filtering the product and optionally drying under vacuum. III. dissolving the wet product of step (II) in single organic solvent or a mixture of two or more organic solvents followed by addition of antioxidant and optionally concentrating the solution by recovery of solvent. IV. addition of mass of step (III) to an anti - solvent or addition of an anti-solvent to the mass of step (III). V. filtering and drying the product by conventional methods to afford amorphous Atorvastatin calcium salt (2:1) of high purity i.e. almost impurity free. According to one embodiment of this invention, the organic amines used in step (c) are amines like N, N-diisopropylethylamine, tert-butyl amine, triethyl amine, N-methyl glucamine etc.
According to other embodiment of this invention, the antioxidant used in step (c), (g), (i), I and III are taken from butylated hydroxyl toluene, butylated hydroxyl anisole, t-butyl hydroquinone, hydroquinone monomethyl ether or some sulphur compounds like l-(mercaρtomethyl) cyclopropane acetic acid, its methyl ester, thiophenol and compounds like chromophore EL etc. It may be pertinent to mention here that employing antioxidant optionally with amine in step (c), (g), & I is new. The use of sulphur compounds as antioxidant in all steps is a new concept.
According to yet other embodiment of this invention, in the binary, ternary or quaternary solvents mixtures used in step (g) & I, the aliphatic alcohols are selected from Ci -C4 aliphatic alcohols preferably methanol, ethanol, propanol, butanol or a mixture thereof; the aliphatic ethers are selected from tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, tert-butyl methyl ether or a mixture thereof. Halogenated aliphatic hydrocarbons are selected from methylene chloride, chloroform, carbon tetrachloride or their mixture.
According to still another embodiment of this invention, the ratio of various solvents in the binary mixture used in step (g) & I is taken as 1-20 : 20-1.
According to another embodiment of this invention, the ratio of various solvents in the ternary mixture used in step (g) & I is taken as 1-20: 1-20: 1-20.
According to yet another embodiment of this invention, the ratio of various solvents in the quaternary mixture used in step (g) & I is taken as 1-15: 1-15: 1-15: 1-15.
Note: the washing of crude or impure atorvastatin calcium (any form) in step (g) & I using binary, tertiary or quaternary mixtures of organic solvent without dissolution of product is new concept.
According to still another embodiment of this invention, the temperature in step (g) & I for washing of Atorvastatin hemi calcium salt of formula (I)5 is ranging from O0C to 1000C.
According to yet another aspect of this invention, the organic solvents used for dissolution of product in step (i) are selected from aliphatic esters like ethyl acetate, propyl acetate, butyl acetate; aliphatic nitrites like acetonitrile, propionitrile; chlorinated hydrocarbons like methylene chloride, chloroform, carbon tetrachloride or a mixture of two or more above mentioned solvents.
According to another aspect of this invention, the anti-solvent used for crystallization of the final product in step (j) & IV are selected from C4-C8 aliphatic long or branched chain hydrocarbons like butane, pentane, hexane, heptane, octane ; aliphatic ethers like diisopropyl ether, t- butylmethyl ether or a mixture of two or more of these solvents. Water can be used as anti- solvent for the crystallization of final product.
According to yet another embodiment of this invention, the drying temperature of product in step (k) & V is ranging from 2O0C to 1000C.
According to another embodiment of this invention, the washing of crude or impure atorvastatin hemi calcium salt using binary, ternary or quaternary mixtures of organic solvents in step (g) & I resulted in the increase in purity from 98.0% to 99.90% i.e. almost impurity free product is obtained.
The present invention will be fully understood from the following examples:
EXAMPLE -1
Preparation of crude Atorvastatin hemicalcium salt
The compound (4R-Cis)- 1 - 1 -dimethylethyl-6-[2-(2-(4-fluorophenyl)-5-(ϊ -methylethyl)~3 - phenyl-4-[(phenylamino)carbonyl]-lH-pyrrol-l-yl]ethyl-2,2-dimethyl-l,3-dioxane-4-acetate
(500g) is dissolved in methanol (12.01tr) at 40-450C. After dissolution, the solution is cooled to 15-200C and 1.5N aq. hydrochloric acid (1.71tr) is added and stirred for 30-36 hrs at 35-400C. Then 15% aq. NaOH solution (1.71tr) is added at 15-2O0C and stirred for 30-36hrs at 35-400C. Activated charcoal (25g) is added and reaction mixture is stirred for 30minutes. The reaction solution is filtered through hyflo bed. The solvent is removed at reduced pressure to reduce the volume to one third and a mixture of methanol (l.Oltr) and water (3.01tr) is added and stirred for 30 minutes. A mixture of n-hexane (l.Oltr), ethyl acetate (l.Oltr) is added, stirred for 15 minutes and aq. layer is separated. The pH of aq. layer is adjusted to 8.0-8.5 and stirred for 30 minutes at 40-450C. To this an aq. calcium acetate solution (65g in 0.51tr of water) is added in one lot slowly followed by addition of N,N-diisopropyIethylamine (25ml) along with butylated hydroxy toluene and seeding with amorphous Atorvastatin hemi calcium salt (5g). The resulting reaction mixture is stirred for 4-5hr at 40-450C. The precipitated solid is filtered followed by washing with a mixture of methanol (0.51tr) and water (2.01tr) to obtain crude Atorvastatin hemi calcium salt (wet) of formula (I). (40Og, on dry basis)
EXAMPLE -2
Preparation of amorphous Atorvastatin hemicalcium salt
To a mixture of methanol - tetrahydrofϊiran - water (400ml:500ml:1.751tr) at 40-450C, wet sample of crude Atorvastatin hemi calcium salt (10Og; on dry basis) from example I is added followed by addition of butylated hydroxy toluene (0.5Og) and the reaction mixture is stirred at 40-450C for 2-3hr. The product is filtered and washed with a mixture of methanol - tetrahydrofuran - water (40ml:50ml: 175ml).
The resulting solid mass is dissolved in methylene chloride (2.01tr) at 25-35°C and aq. layer is separated and butylated hydroxy toluene (0.50g) is added to the organic layer. Then organic layer is concentrated up to about 800ml. at 40-420C at atmospheric pressure.
The concentrated organic layer is added dropwise into precooled diisopropyl ether (2.5ltr) at 10- 15°C under stirring in 45minutes (Alternatively diisopropyl ether can be added to the concentrated methylene chloride layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-500C in a vacuum dryer for 24-48hr and 65g atorvastatin hemi calcium salt in amorphous form was obtained. HPLC purity : 99.92%; Assay (OAB, HPLC) : 99.80%
EXAMPLE -3 Preparation of amorphous Atorvastatin hemicalcium salt
To a mixture of isopropanol - acetonitrile - water (500ml:400ml:1.75Itr) at 40-450C, wet sample of crude Atorvastatin hemi calcium salt (10Og; on dry basis) from example I is added followed by addition of butylated hydroxy toluene and the reaction mixture is stirred at 40-450C for 2-3hr. The product is filtered and washed with a mixture of isopropanol - acetonitrile - water (50ml:40mi: 175ml).
The resulting solid mass is dissolved in methylene chloride (2.01tr) at 25-350C and aq. layer is separated and butylated hydroxy toluene (0.50g) is added to the organic layer. Then organic layer is concentrated up to about 800ml. at 40-420C at atmospheric pressure. The concentrated organic layer is added dropwise into precooled diisopropyl ether (2.51tr) at 10-150C under stirring in 45minutes (Alternatively diisopropyl ether can be added to the concentrated methylene chloride layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-500C in a vacuum dryer for 24-48 hr and 56g of atorvastatin hemi calcium salt in amorphous form was obtained.
HPLC purity: 99.75%; Assay (OAB, HPLC) : 99.50%
EXAMPLE -4
Preparation of amorphous Atorvastatin calcium salt To a mixture of tert-butanol - acetonitrile - water (500ml:400ml:1.751tr) at 40-450C, wet sample of crude Atorvastatin hemi calcium salt (10Og; on dry basis) from example I is added followed by addition of butylated hydroxy toluene (0.50g) and the reaction mixture is stirred at 40-450C for 2-3hr. The product is filtered and washed with a mixture of tert-butanol - acetonitrile - water
(50ml:40ml: 175ml). The resulting solid mass is dissolved in methylene chloride (2.01tr) at 25-35°C and aq. layer is separated and butylated hydroxy toluene (0.50g) is added to the organic layer. Then organic layer is concentrated up to about 800ml. at 40-420C at atmospheric pressure.
The concentrated organic layer is added dropwise into precooled diisopropyl ether (2.51tr) at
10-150C under stirring in 45minutes (Alternatively diisopropyl ether can be added to the concentrated methylene chloride layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-500C in a vacuum dryer for 24-48hr and 50g of atorvastatin hemi calcium salt in amorphous form was obtained.
HPLC purity: 99.80%; Assay (OAB, HPLC): 99.50%
EXAMPLE -5
Preparation of amorphous Atorvastatin hemicalcium salt
To a mixture of methylene chloride - diisopropyl ether - methanol (300ml: 1.51tr:300ml) at 40-
45°C, wet sample of crude Atorvastatin hemi calcium salt (10Og; on dry basis) from example I is added followed by addition of butylated hydroxy toluene (0.5Og) and the reaction mixture is stirred at 40-450C for 2-3hr. The product is filtered and washed with a mixture of methylene chloride - diisopropyl ether - methanol (30ml:150ml:30ml). The resulting solid mass is dissolved in methylene chloride (2.01tr) at 25-35°C and aq. layer is separated and butylated hydroxy toluene (0.5Og) is added to the organic layer. Then organic layer is concentrated up to about 800ml. at 40-420C at atmospheric pressure.
The concentrated organic layer is added dropwise into precooled diisopropyl ether (2.51tr) at 10-150C under stirring in 45minutes (Alternatively diisopropyl ether can be added to the concentrated methylene chloride layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-500C in a vacuum dryer for 24-48hr and 65g atorvastatin hemi calcium salt in amorphous form was obtained. HPLC purity : 99.75%; Assay (OAB, HPLC) : 99.40%
EXAMPLE -6
Preparation of Amorphous Atorvastatin calcium salt
To a mixture of methanol - tetrahydrofuran - water (400ml:500ml:1.751tr) at 40-450C, crystalline Atorvastatin hemi calcium salt (10Og) is added followed by addition of butylated hydroxy anisole (0.50g) and the reaction mixture is stirred at 40-450C for 2-3hr. The product is filtered and washed with a mixture of methanol - tetrahydrofuran - water (40ml:50ml: 175ml). The resulting solid mass is dissolved in methylene chloride (2.01tr) at 25-35°C and aq. layer is separated and butylated hydroxy anisole (0.50g) is added to the organic layer. Then organic layer is concentrated up to about 800ml. at 40-420C at atmospheric pressure. The concentrated organic layer is added dropwise into precooled diisopropyl ether (2.51tr) at 10-150C under stirring in 45minutes (Alternatively diisopropyl ether can be added to the concentrated methylene chloride layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-500C in a vacuum dryer for 24-48hr and 65g atorvastatin hemi calcium salt in amorphous form was obtained.
HPLC purity: 99.90%; Assay (OAB, HPLC): 99.70%
EXAMPLE -7
Preparation of Amorphous Atorvastatin calcium salt To a mixture of isopropanol - acetonitrile - water (500ml:400ml:1.751tr) at 40-450C, crystalline Atorvastatin hemi calcium salt (10Og) is added followed by addition of butylated hydroxy anisole (0.50g) and the reaction mixture is stirred at 40-450C for 2-3hr. The product is filtered and washed with a mixture of isopropanol - acetonitrile - water (50ml:40ml:175ml). The resulting solid mass is dissolved in methylene chloride (2.01tr) at 25-35°C and aq. layer is separated and butylated hydroxy anisole (0.5Og) is added to the organic layer. Then organic layer is concentrated up to about 800ml. at 40-420C at atmospheric pressure.
The concentrated organic layer is added drop wise into pre cooled diisopropyl ether (2.51tr) at 10-150C under stirring in 45minutes (Alternatively diisopropyl ether can be added to the concentrated methylene chloride layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-500C in a vacuum dryer for 24-48hr and 56g atorvastatin hemi calcium salt in amorphous form was obtained. HPLC purity: 99.80%; Assay (OAB, HPLC): 99.65%
EXAMPLE -8
Preparation of Amorphous Atorvastatin hemicalcium salt
To a mixture of tert-butanol - acetonitrile - water (500ml:400ml:1.751tr) at 40-450C, crystalline
Atorvastatin hemi calcium salt (10Og) is added followed by addition of butylated hydroxy anisole (0.5Og) and the reaction mixture is stirred at 40-450C for 2-3hr. The product is filtered and washed with a mixture of ter-butanol - acetonitrile - water (50ml:40ml:175mI). The resulting solid mass is dissolved in methylene chloride (2.0Itr) at 25-35°C and aq. layer is separated and butylated hydroxy anisole (0.50g) is added to the organic layer. Then organic layer is concentrated up to about 800ml. at 40-420C at atmospheric pressure. The concentrated organic layer is added drop wise into pre cooled diisopropyl ether (2.51tr) at 10-150C under stirring in 45minutes (Alternatively diisopropyl ether can be added to the concentrated methylene chloride layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-500C in a vacuum dryer for 24-48hr and 5Og of atorvastatin hemi calcium salt in amorphous form was obtained. HPLC purity: 99.75%; Assay (OAB, HPLC): 99.60%
EXAMPLE -9
Preparation of Amorphous Atorvastatin calcium salt
To a mixture of methylene chloride - diisopropyl ether - methanol (300ml: 1.51tr:300ml) at 40- 45°C, crystalline Atorvastatin hemi calcium salt (10Og) is added followed by addition of butylated hydroxy anisole (0.50g) and the reaction mixture is stirred at 40-450C for 2-3hr. The product is filtered and washed with a mixture of methylene chloride - diisopropyl ether - methanol (30ml:150ml:30ml). The resulting solid mass is dissolved in methylene chloride (2.01tr) at 25-35°C and aq. layer is separated and butylated hydroxy anisole (0.5Og) is added to the organic layer. Then organic layer is concentrated up to about 800ml. at 40-42°C at atmospheric pressure. The concentrated organic layer is added drop wise into pre cooled diisopropyl ether (2.51tr) at 10-150C under stirring in 45minutes (Alternatively diisopropyl ether can be added to the concentrated methylene chloride layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-500C in a vacuum dryer for 24-48hr and 65 g atorvastatin hemi calcium salt in amorphous form was obtained. HPLC purity: 99.80%; Assay (OAB, HPLC): 99.55%
EXAMPLE -10
Preparation of amorphous Atorvastatin calcium salt
To a mixture of methanol - tetrahydrofuran - water (400ml:500ml:1.751tr) at 40-450C, wet sample of crude Atorvastatin hemi calcium salt (10Og; on dry basis) from example I is added followed by addition of butylated hydroxy anisole (0.50g) and the reaction mixture is stirred at 40-450C for 2-3hr. The product is filtered and washed with a mixture of methanol - tetrahydrofuran - water (40ml:50ml: 175ml).
The resulting solid mass is dissolved in a mixture of acetonitrile (0.5ltr) and methylene chloride (2.01tr) at 25-350C and butylated hydroxy anisole (0.50g) is added to the organic layer. Then organic layer is concentrated up to about 800ml. at 40-500C at atmospheric pressure. The concentrated organic layer is added dropwise into precooled diisopropyl ether (2.51tr) at 10- 150C under stirring in 45minutes (Alternatively diisopropyl ether can be added to the concentrated methylene chloride layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-500C in a vacuum dryer for 24-48hr and 6Og atorvastatin calcium salt in amorphous form was obtained.
HPLC purity: 99.90%; Assay (OAB, HPLC): 99.60%
EXAMPLE -I l
Preparation of amorphous Atorvastatin hemicalcium salt To a mixture of tetrahydrofuran - acetonitrile - water (500ml:400ml:1.751tr) at 40-450C, wet sample of crude Atorvastatin hemi calcium salt (10Og; on dry basis) from example I is added followed by addition of butylated hydroxy anisole and the reaction mixture is stirred at 40-450C .
12
for 2-3hr. The product is filtered and washed with a mixture of tetrahydrofuran - acetonitrile - water (50ml:40ml:175ml).
The resulting solid mass is dissolved in a mixture of ethylacetate (3.01tr) & methanol (l.Oltr) at 25-35°C and butylated hydroxy anisole (0.5Og) is added to it. Then organic layer is concentrated up to about 800ml. at 40-50°C at reduced pressure. The concentrated organic layer is added dropwise into precooled n-hexane (2.51tr) at 10-150C under stirring in 45minutes (Alternatively n-hexane can be added to the concentrated organic layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-500C in a vacuum dryer for 24-48hr and 55g of atorvastatin calcium salt in amorphous form was obtained. HPLC purity: 99.85%; Assay (OAB, HPLC): 99.50%
EXAMPLE -12
Preparation of amorphous Atorvastatin calcium salt
To a mixture of tert-butanol - acetonitrile - water (500ml:400ml:1.751tr) at 40-450C, wet sample of crude Atorvastatin hemi calcium salt (10Og; on dry basis) from example I is added followed by addition of hydroquinone monomethyl ether (0.50g) and the reaction mixture is stirred at 40-
45°C for 2-3hr. The product is filtered and washed with a mixture of tert-butanol - acetonitrile - water (50ml:40ml: 175ml).
The resulting solid mass is dissolved in ethyl acetate (2.01tr) at 25-350C, aq. layer is separated and hydroquinone monomethyl ether (0.50g) is added to the organic layer. Then organic layer is concentrated up to about 800ml. at 40-500C at reduced pressure.
The concentrated organic layer is added dropwise into pre cooled n-heptane (2.51tr) at 10-150C under stirring in 45minutes (Alternatively n-heptane can be added to the concentrated ethyl acetate layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-500C in a vacuum dryer for 24-48hr and 50g of atorvastatin hemi calcium salt in amorphous form was obtained.
HPLC purity: 99.70%; Assay (OAB, HPLC): 99.60%
EXAMPLE -13
Preparation of amorphous Atorvastatin calcium salt
To a mixture of methylene chloride - diisopropyl ether - methanol (300ml: 1.51tr:300ml) at 40-
45°C, wet sample of crude Atorvastatin hemi calcium salt (10Og; on dry basis) from example I is added followed by addition of propyl gallate (0.5Og) and the reaction mixture is stirred at 40- 45°C for 2-3hr. The product is filtered and washed with a mixture of methylene chloride - diisopropyl ether - methanol (30ml:150ml:30ml).
The resulting solid mass is dissolved in acetonitrile (l.Oltr) at 25-35°C and propyl gallate (0.5Og) is added to it. Then organic layer is concentrated up to about 800ml. at 40-500C at reduced pressure.
The concentrated organic layer is added dropwise into pre cooled DM water (2.51tr) at 10-150C under stirring in 45minutes (Alternatively precooled DM water can be added to the concentrated organic layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-500C in a vacuum dryer for 24-48hr and 6Og atorvastatin calcium salt in amorphous form was obtained. HPLC purity: 99.70%; Assay (OAB, HPLC): 99.40%
EXAMPLE -14
Preparation of Amorphous Atorvastatin calcium salt To a mixture of methanol - tetrahydrofuran - water (400ml:500ml:1.751tr) at 40-450C, wet sample of crude Atorvastatin hemi calcium salt (10Og) is added followed by addition of t-butyl hydroquinone (0.50g) and the reaction mixture is stirred at 40-450C for 2-3hr. The product is filtered and washed with a mixture of methanol - tetrahydrofuran - water (40ml:50ml: 175ml).
The resulting solid mass is dissolved in a mixture of acetonitrile (0.501tr) and methylene chloride (2.01tr) at 25-350C and the solvent is removed at reduced pressure. The resulting solid is further dried under vacuum at 40-450C for 12-16hr to get the product.
HPLC purity: 99.70%; Assay (OAB, HPLC): 99.30%
EXAMPLE -15 Preparation of Amorphous Atorvastatin calcium salt
To a mixture of tetrahydrofuran - acetonitrile - water (500ml:400ml:1.751tr) at 40-450C, crystalline Atorvastatin hemi calcium salt (10Og) is added followed by addition of butylated hydroxy anisole (0.50g) and the reaction mixture is stirred at 40-450C for 2-3hr. The product is filtered and washed with a mixture of tetrahydrofuran - acetonitrile - water (50ml:40ml: 175ml). The resulting solid mass is dissolved in toluene (2.01tr) at 25-350C and aq. layer is separated and butylated hydroxy anisole (0.5Og) is added to the organic layer. Then organic layer is concentrated up to about 800ml. at 50-600C at reduced pressure. The concentrated organic layer is added drop wise into pre cooled n-heptane (2.51tr) at 10-150C under stirring in 45minutes (Alternatively n-heptane can be added to the concentrated toluene layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-500C in a vacuum dryer for 24-48hr and 56g atorvastatin hemi calcium salt in amorphous form was obtained. HPLC purity: 99.60%; Assay (OAB5 HPLC): 99.65%
EXAMPLE -16
Preparation of Amorphous Atorvastatin calcium salt
To a mixture of tert-butanol - acetonitrile - water (500ml:400ml:1.751tr) at 40-450C, crystalline Atorvastatin hemi calcium salt (10Og) is added followed by addition of butylated hydroxy anisole (0.5Og) and the reaction mixture is stirred at 40-450C for 2-3hr. The product is filtered and washed with a mixture of tert-butanol - acetonitrile - water (50ml:40ml: 175ml). The resulting solid mass is dissolved in toluene (2.01tr) at 25-35°C and aq. layer is separated and butylated hydroxy anisole (0.50g) is added to the toluene layer. Then organic layer is concentrated up to about 800ml. at 50-600C at reduced pressure. The concentrated organic layer is added drop wise into pre cooled n-hexane (2.51tr) at 10-150C under stirring in 45minutes (Alternatively n-hexane can be added to the concentrated toluene layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-500C in a vacuum dryer for 24-48hr and 5Og of atorvastatin hemi calcium salt in amorphous form was obtained. HPLC purity: 99.75%; Assay (OAB, HPLC): 99.30%
EXAMPLE -17
Preparation of Amorphous Atorvastatin calcium salt To a mixture of methylene chloride - diisopropyl ether - methanol (300ml: 1.51tr:300ml) at 40- 450C, crystalline Atorvastatin hemi calcium salt (10Og) is added followed by addition of butylated hydroxy toluene (0.5Og) and the reaction mixture is stirred at 40-450C for 2-3hr. The product is filtered and washed with a mixture of methylene chloride - diisopropyl ether - methanol (30ml:150ml:30ml). The resulting solid mass is dissolved in toluene (2.01tr) at 25-350C and aq. layer is separated and butylated hydroxy anisole (0.50g) is added to the toluene layer. Then organic layer is concentrated up to about 800ml. at 50-600C at reduced pressure. The concentrated organic layer is added drop wise into pre cooled diisopropyl ether (2.51tr) at 10-150C under stirring in 45minutes (Alternatively diisopropyl ether can be added to the concentrated methylene chloride layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-500C in a vacuum dryer for 24-48hr and 65g atorvastatin hemi calcium salt in amorphous form was obtained. HPLC purity: 99.60%; Assay (OAB, HPLC): 99.25%
EXAMPLE -18
Preparation of Amorphous Atorvastatin calcium salt
To a mixture of methylene chloride - diisopropyl ether - methanol (300ml: 1.51tr:300ml) at 40-
45°C, crystalline Atorvastatin hemi calcium salt (10Og) is added followed by addition of butylated hydroxy toluene (0.5Og) and the reaction mixture is stirred at 40-450C for 2-3hr. The product is filtered and washed with a mixture of methylene chloride - diisopropyl ether - methanol (30ml:150ml:30ml). The product was dried at 40-500C under vacuum for 24-48 hrs to get 65 g of the product. HPLC purity: 99.60%; Assay (OAB, HPLC): 99.25%
ADVANTAGES
1. The main advantage of the purification processes described above have that they resulted in the increased purity of the product i.e. amorphous Atorvastatin hemi calcium salt of formula (I) obtained is almost impurity free along with satisfactory yield. 2. The increased purity of the product along with the use of amine and antioxidant results in the increased stability of amorphous Atorvastatin calcium salt.
The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

Claims

CLAIMS:
1. An improved process for the preparation of amorphous atorvastatin hemi calcium, [R- (R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(l-methyl ethyl)-3-phenyI-4-
[(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid calcium salt of formula 1
Figure imgf000017_0001
Formula I which comprises,
(a) obtaining an aq. solution of Atorvastatin sodium salt by reacting compound of formula (II) with aq. hydrochloric acid and aq. caustic solution in methanol followed by washing of aq. solution of Atorvastatin sodium with a 1:1 mixture of ethyl acetate-hexane,
Figure imgf000017_0002
Formula II
(b) addition of organic amine and an antioxidant,
(c) addition of the Atorvastatin sodium salt solution to an aqueous calcium chloride or calcium acetate solution,
(d) seeding with amorphous atorvastatin calcium,
(e) filtering the slurry to get wet cake,
(f) washing of wet cake by stirring in a binary, tertiary or quaternary mixture of aliphatic alcohol, aliphatic ether, aliphatic nitrile, halogenated aliphatic hydrocarbon and water using antioxidant,
(g) filtering the product and optionally drying under vacuum, (h) dissolving the wet product of step (g) in single organic solvent or a mixture of two or more organic solvents followed by addition of antioxidant and optionally concentrating the solution by recovery of solvent, (i) addition of mass of step (h) to an anti - solvent or addition of an anti-solvent to the mass of step (h), G) filtering and drying the product by conventional methods to afford amorphous
Atorvastatin hemi calcium salt of formula (I) of high purity.
2. A purification process for the preparation of amorphous Atorvastatin calcium salt of formula (I) which comprises; (a) washing of crystalline or amorphous Atorvastatin calcium of formula (I) by stirring in a binary, tertiary or quaternary mixture of aliphatic alcohol, aliphatic ether, aliphatic nitrile, halogenated aliphatic hydrocarbon and water using antioxidant,
(b) filtering the product and optionally drying under vacuum,
(c) dissolving the wet product of step (b) in single organic solvent or a mixture of two or more organic solvents followed by addition of antioxidant and optionally concentrating the solution by recovery of solvent,
(d) addition of mass of step (b) to an anti - solvent or addition of an anti-solvent to the mass of step (b),
(e) filtering and drying the product by conventional methods to afford almost impurity free amorphous Atorvastatin calcium salt (2:1).
3. A process as claimed in claim 1 wherein the amine are tertiary amines like N,N- diisopropylethylamine, tert-butyl amine or triethyl amine.
4. A process as claimed in claim land 2 wherein the antioxidant are taken from butylated hydroxyl toluene, butylated hydroxyl anisole, t-butyl hydroquinone, hydroquinone monomethyl ether or some sulphur compounds like l-(mercaρtom ethyl) cyclopropane acetic acid, l-(mercaptomethyl) cyclopropane acetic acid methyl ester, thiophenol or a mixture there of.
5. A process as claimed in claim land 2 wherein the binary, tertiary or quaternary solvents mixture consist of the aliphatic alcohols selected from C1-C4 aliphatic alcohols preferably methanol, ethanol, propanol, butanol ; the aliphatic ethers selected from tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, tert-butyl methyl ether, halogenated aliphatic hydrocarbons selected from methylene chloride, chloroform, carbon tetrachloride or a mixture thereof.
6. A process as claimed in claim land 2 wherein the ratio of various solvents in the binary ternary or quaternary mixtures is taken from 0-50 times with respect to each other.
7. A process as claimed in claim land 2 wherein the organic solvent used for dissolution of product are selected from aliphatic esters like ethyl acetate, propyl acetate, butyl acetate; aliphatic nitriles like acetonitrile, propionitrile; chlorinated hydrocarbons like methylene chloride, chloroform, carbontetrachloride or a mixture of two or more of above mentioned solvents.
8. A process as claimed in claim land 2 wherein the anti-solvent used for crystallization of the final product are selected from C4-C8 aliphatic long or branched chain hydrocarbons like butane, pentane, hexane, heptane, octane ; aliphatic ethers like diisopropyl ether, t- butylmethyl ether or a mixture of two or more of above mentioned solvents.
9. A process as claimed in claim land 2 wherein the anti-solvent is water.
10. A process as claimed in claim land 2 wherein the drying temperature of product is ranging from 2O0C to 1000C.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011131605A1 (en) 2010-04-19 2011-10-27 Dsm Ip Assets B.V. Production of atorvastatin low in ether impurities
WO2011131601A1 (en) 2010-04-19 2011-10-27 Dsm Ip Assets B.V. Production of atorvastatin low in lactone impurities
WO2012034958A1 (en) 2010-09-16 2012-03-22 Dsm Sinochem Pharmaceuticals Netherlands B.V. Esters of hexanoic acids as intermediates for the preparation of atorvastatin
CN109142586A (en) * 2018-10-09 2019-01-04 河南师范大学 A kind of method of liquid chromatography for measuring Atorvastatin calcium intermediate A TS-9 and its impurity B content

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050032880A1 (en) * 2003-06-12 2005-02-10 Lorenz Douglas A. Process for forming amorphous atorvastatin
US20050119493A1 (en) * 2001-08-31 2005-06-02 Sanjay Suri Process for the preparation of amorphous atorvastin calcium salt (2:1)
US7151183B2 (en) * 2000-11-30 2006-12-19 Teva Pharmaceutical Industries Ltd. Processes for preparing amorphous atorvastatin hemi-calcium

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7151183B2 (en) * 2000-11-30 2006-12-19 Teva Pharmaceutical Industries Ltd. Processes for preparing amorphous atorvastatin hemi-calcium
US20050119493A1 (en) * 2001-08-31 2005-06-02 Sanjay Suri Process for the preparation of amorphous atorvastin calcium salt (2:1)
US20050032880A1 (en) * 2003-06-12 2005-02-10 Lorenz Douglas A. Process for forming amorphous atorvastatin

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011131605A1 (en) 2010-04-19 2011-10-27 Dsm Ip Assets B.V. Production of atorvastatin low in ether impurities
WO2011131601A1 (en) 2010-04-19 2011-10-27 Dsm Ip Assets B.V. Production of atorvastatin low in lactone impurities
CN103108863A (en) * 2010-04-19 2013-05-15 中化帝斯曼制药有限公司荷兰公司 Production of atorvastatin low in ether impurities
CN103108863B (en) * 2010-04-19 2015-08-19 中化帝斯曼制药有限公司荷兰公司 The preparation of the atorvastatin of low ether impurity
WO2012034958A1 (en) 2010-09-16 2012-03-22 Dsm Sinochem Pharmaceuticals Netherlands B.V. Esters of hexanoic acids as intermediates for the preparation of atorvastatin
CN109142586A (en) * 2018-10-09 2019-01-04 河南师范大学 A kind of method of liquid chromatography for measuring Atorvastatin calcium intermediate A TS-9 and its impurity B content

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