FORM - 2 THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
PROVISIONAL
Specification
(See section 10 and rule 13)
PROCESS FOR THE PREPARATION OF AMORPHOUS ATORVASTATIN CALCIUM
M. J. INSTITUTE OF RESEARCH
A Research Institute Organized under the laws of India of 113, Jolly Maker Chambers-II, Nariman Point, Mumbai 400 021,
Maharashtra, India
THE FOLLOWING SPECIFICATION DESCRIBES THE INVENTION.

The present invention relates in process for forming amorphous Atorvastatin hemi-calcium salt a well known drug substance belonging to statin group.
In particular, this invention describes preparation of amorphous product from (4R-Cis)-1,1 -Dimethylethyl-6-[2[2-(4-fluorophenyl-5-( 1 -methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrol-1 -yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate of formula II with an improved process.
Back ground of the invention:
The active pharmaceutical ingredient known as Atorvastatin hemi-calcium
salt, which is chemically known as [R-(R*,R*)]-2-(4-fluorophenyl)-β-δ-
dihydroxy-5-[l-methyl-ethyl]-3-phenyl-4-[(phenylamino) carbonyl-1H-
pyrrole-1-heptanoic acid hemi-calcium salt is a member of the class of drugs called statins.
The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate is an early and rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by the enzyme HMG-CoA reductase. Statins inhibit HMG-CoA reductase from catalyzing this conversion. As such, statins are considered as potent lipid lowering agents.
Atorvastatin in its hemi-calcium salt form is an excellent inhibitor of the enzyme HMG-CoA reductase, thus it is useful as a hypolipidemic and hypocholesterolemic active pharmaceutical ingredient for the therapy of lipidic metabolic disorders. It is used successfully for preventing and for treating coronary heart disease.
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The hemi-calcium salt of atorvastatin has been prepared in past using several synthetic methods, and it is reported to occur in various polymorphic forms which can be crystalline or amorphous in its physical characteristics.
The preparation of Atorvastatin and its key intermediates which are required in the synthesis are described in various patents such as US Pat nos. 5,003,080; 5,092,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,245,793; 5,280,126; 5,342,952; 5,397,792.
The following account provides a brief review regarding preparation of different forms of atorvastatin hemi-calcium salt, in particular, the amorphous form:
WO 02/43732 A1 describes preparation of several new forms of Atorvastatin hemi-calcium salt as well as new processes in preparation of the same. These forms mainly include various crystalline forms and solvates and hydrates thereof. A process for preparation of amorphous atorvastatin has also been described.
WO 03/068739 A1 describes a method for preparation of atorvastatin hemi-calcium amorphous by interacting a solution containing alkali or ammonium type salt of atorvastatin, with a solution containing calcium ions as a calcium salt, calcium hydroxide etc. The amorphous form is obtained without isolation of any intermediate crystalline or other such forms.
The patent WO 2004/085391 A1 relates to a new process for synthesis of the amorphous variety wherein a salt of atorvastatin acid is first formed with a
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basic amino acid like L-lysine or L-arginine. The solution of such a salt in a mixture of aqueous organic solvent is then treated with a solution of calcium salt like calcium acetate or calcium chloride. Atorvastatin hemi-calcium salt is isolated by filtration as an amorphous product.
WO 2005/090301 A1 details a new crystalline form R of atorvastatin hemi-calcium salt as well as its hydrates this crystalline form R was also converted to its amorphous form. Further, pharmaceutical compositions with this new crystalline form R along with pharmaceutically acceptable excipients are also mentioned.
WO 02/083637 A1 relates to another process for preparing amorphous atorvastatin calcium in presence of aqueous methanollic solvent system. The process involves acidic and alkaline hydrolysis of diol protected tert butyl ester i.e. compound of formula (I). The crude amorphous product is isolated first which is then purified by addition of its methanollic solution in aqueous medium.
US patent 6,613,916 B2 deals with conversion of crystalline atorvastatin calcium into the amorphous form. The crystalline product is first dissolved in relatively polar solvents like methanol, alcohol, acetone etc., partially concentrated and then added into another relatively less polar solvent like ether so as to obtain the amorphous product isolated by filtration. Another US patent 2003/0149279 A1 also describes similar process wherein the crystalline product is first dissolved in a non-hydroxyllic solvent like tetrahydrofuran followed by treatment with relatively non polar anti-solvent like a hydrocarbon.
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US patent application 2004/0242670 relates to a process for preparation of the amorphous form by dissolving the crystalline product in a hydroxyllic solvent followed by Complete removal of the solvent by spray drying. The resultant product was found to be of amorphous character. It is also been shown that a crystalline product can be converted into its amorphous form by extended pulverization of grinding. Similar spray drying process to obtain amorphous atorvastatin hemi-calcium salt is also reported in US patent 2005/0032880 A1.
Another process for preparation of amorphous atorvastatin calcium, describe as per US patent 2005/0165242 A1, deals with converting the intermediate atorvastatin lactone into its sodium salt by alkaline hydrolysis. This solution of sodium salt is next treated with aqueous solution of a calcium salt like calcium chloride or calcium acetate, which may be added up with seeds of the amorphous material. Resultant solid is isolated by filtration and drying to obtain amorphous product.
WO 03/099785 indicates the use of aliphatic acyclic ketone type solvent like acetone, butanone, pentanone, hexanone etc. , followed by dissolution at elevated temperature, filtration and finally desolventisation. Similarly, US patents 6,087,511 and 6,274,740 describe the preparation of atorvastatin calcium amorphous from the crystalline form I by dissolution in a non-hydroxyllic solvent followed by filtration and complete de-solventization in vacuum. US patent 2006/0106230 A1 also describes preparation of the amorphous product by dissolution in certain organic solvents comprised of mixture of hydroxyllic solvent with other ketonic or ester type solvents and then removal of the solvent by techniques like spray drying, rapid vacuum evaporation and thin film evaporation.
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According to WO 2006/048888 the amorphous substance can be prepared by using solvents like 1,4-dioxane; acetonitrile; toluene; anisole; tert-butanol etc. in combination with anti-solvents like hydrocarbons and ethers. The amorphous product is isolated by usual vacuum filtration and vacuum drying.
A new process according to WO 2006/021969 A1 employs alkaline hydrolysis of the diol protected tert butyl ester i.e. compound of formula (I) in tetrahydrofuran-water mixture. Resultant sodium salt of atorvastatin is isolated by filtration followed by re-dissolution in an organic ester solvent like ethyl acetate. The ethyl acetate solution is next treated with aqueous solution of calcium salt, separated and then desolventized to obtain the amorphous product.
According to US patent 6,646,133 B1 amorphous atorvastatin calcium is obtained from the crude substance by dissolving it in alcoholic solvent followed by filtration and cooling. The precipitated amorphous substance is isolated by filtration. The patent suggests that it may not be essential to have totally non-hydroxyllic solvent for obtaining the amorphous product.
US patent 6,867,306 describes a new intermediate viz. phenyl boronate diol protecting pyrrole derivative for synthesis of atorvastatin calcium. This is hydrolysed to obtain atorvastatin sodium in aqueous solution, and then converted into atorvastatin acid followed by its extraction in an organic solvent. The acid is next derivatised to its ammonium salt, purified by crystallization. It is re-dissolved in an organic solvent mixture, and finally treated with aqueous calcium salt solution, whereby, amorphous atorvastatin calcium precipitates out.
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US patent application 2006/0128971 describes preparation of amorphous atorvastatin hemi-calcium salt by use of solvents like tetrahydrofuran, dimethyl acetamide, dimethyl sulfoxide etc. to dissolve crude amorphous atorvastatin calcium and then adding the solution in demineralised water. The solid product is filtered and vacuum dried to obtain purified amorphous product.
US patent application 2006/0142592 A1, describes the preparation of certain crystalline as well as amorphous forms. Further, preparation of an impurity substance atorvastatin calcium epoxy dihydroxy is also mentioned. Novel salt forms of atorvastatin acid and their method of preparation are described in WO 2005/105738.
Atorvastatin salts are prepared while using basic or amine compound like ammonia, benethamine, benzathime, dibenzyl amine, diethyl amine, erbumine, L-lisyne, morpholine, piperazine . These salts have also been shown to be useful as agents for treatment of hyperlipidemia, hypercholesterolemia, osteoporosis, benign prostatic hyperplasia and Alzheimer's Disease.

OH OH
COO
r^,

Ca+2

Formula -1
7

Formula - II


PhHN

Formula - III

Formula - IV
8

OH OH O
"\^ r<^N

Formula - V

OH OH
COO"Na+
r<^

Formula - VI
Summary of the Invention:
The present invention relates to an improved process for preparation of atorvastatin hemi-calcium salt in its amorphous form. The amorphous form is considered advantageous in pharmaceutical formulations.
The present invention disclose a process for preparation of amorphous form of atorvastatin hemi-calcium salt of formula I [R-(R*,R*)]-2(4-fluorophenyl)-P,8-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole- 1-heptanoic acid calcium salt using an intermediate compound of
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formula II, (4R-Cis)-1,1 -Dimethylethyl-6-[2[2-(4-fluorophenyl-5-( 1 -
methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-l-yl]ethyl]-2,2-
dimethyl-l,3-dioxane-4-acetate which comprises the following steps
i ] two stage sequential hydrolysis in presence of first acidic and then alkaline
media,
ii] in-process purifications involving solvent extraction and treatment with
activated carbon,
iii] precipitation by mixing with low polar organic solvents containing low
concentration of silicone agents, under controlled temperature conditions and
inert atmosphere; and
iv] isolation of the product by filtration under inert atmosphere, vacuum
drying at controlled temperature and storage under inert atmosphere at
controlled and lower temperature.
Typically, the sequential acidic and alkaline hydrolysis of compound of formula II is carried out in organic solvents like methanol, ethanol, tetrahydrofuran or mixtures thereof.
Typically, the reaction mass containing the diol ester of formula V is purified by treatment with activated carbon.
Typically, the aqueous solution of atorvastatin sodium of formula VI after purification by solvent extraction, is treated with a source of Ca++ ions like calcium acetate, calcium hydroxide or calcium chloride to obtain atorvasstatin hemi-calcium salt.
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Typically, the solvent used for in-situ dissolution of atorvastatin hemi-calcium salt is an alkyl ester of relatively smaller carbon chain alcohols like methanol, ethanol, n-propanol, isopropanol, n-butanol and carboxylic acids like formic, acetic, propionic or butyric acid, and mixtures thereof.
Typically, the solution of atorvastatin hemi-calcium salt in an ester is predicted with organic solvent like tetrahydrofuran, isopropanol, ethanol, and n-propanol.
Typically, the precipitation of amorphous atorvastatin hemi-calcium salt from its solution in organic solvent, is carried out by mixing with relatively less polar linear or cyclic hydrocarbons with C1 to C8 carbon atoms and mixtures thereof. Preferabl among these are pentane, hexane, heptane, cyclohexane, methylcyclohexane and toluene.
Typically, the hydrocarbon solvents and mixtures there of are mixed with linear alkyl ethers of formula R1 -O-R2 with preferably C1 to C4 carbon atoms.
Typically, the organic solvents are added up with pharmaceutically acceptable silicone agents like siloxane polymers, preferably polydimethyl silixone and simethicone.
Typically, the concentration of silicone agents in the precipitation solvent medium is maintained at 0.05% to 0.15% by weight of the volume of the solvent medium.
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Typically, the solvent medium for precipitation is maintained between 45°C to (-) 65°C, preferably between 30°C to (-)50°C, before addition of atorvastatin hemi-calcium salt solution in an organic solvent.
Typically, the product atorvastatin hemi-calcium salt is precipitated under inert atmosphere with nitrogen gas.
Typically, the product atorvastatin hemi-calcium salt is dried in vacuum at 30°C to 55°C, preferably at 35°C to 45°C and then stored under inert nitrogen gas atmosphere, under control storage temperature of 2°C to 8°C.
The process, according to this invention, affords the required product with good purity and stability. It consists in converting the intermediate compound of formula II (4R-Cis)-1,1-Dimethylethyl-6-[2[2-(4-fluorophenyl-5-(l-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrol-l-yl]ethyl]-2,2-dimethyl-l,3-dioxane-4-acetate by sequential acid and alkaline hydrolysis to atorvastatin sodium of formula VI, which is in-situ purified and converted to atorvastatin calcium in an organic solvent. After re-purification, it is mixed with relatively low polar organic solvents containing low concentration of silicone agents at relatively lower temperatures under inert atmosphere. Precipitated amorphous product is then isolated by vacuum filtration under inert atmosphere, dried in vacuum at controlled temperature and stored under inert atmosphere at controlled temperature.
This method provides atorvastatin hemi-calcium salt with homogenous amorphous character, high purity and improved stability character. This process can be scaled-up for industrial manufacturing.
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Detailed description of the invention:
The present invention describes an improved process for preparation of amorphous form of atorvastatin hemi-calcium salt, compound of formula I which is beneficial for application in pharmaceutical preparation. The product obtained is homogenously amorphous and shows consistently good purity level and stability characteristics. The said process can be scaled up easily to produce the material commercially.
The present process consists in preparation of the amorphous form while utilizing the intermediate compound (4R-Cis)-1,1-Dimethylethyl-6-[2[2-(4-fluorophenyl-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-l,3-dioxane-4-acetate of formula (II). Compound of formula (II) is sequentially hydrolysed in presence of organic solvent like methanol, ethanol, tetrahydrofuran or mixtures thereof, preferably methanol or tetrahydrofuran using acidic and alkaline media, to open up the protected ketal generating the diol compound of formula V and to hydrolyse the tert-butyl ester of compound of formula V yielding compound of formula VI respectively, as per previously reported procedures. After completion of the first step of acidic hydrolysis, the solution containing intermediate diol ester of formula V is purified by treatment with activated carbon. The purified solution is next hydrolysed with aqueous alkali to generate solution of atorvastatin sodium salt of formula VI. This solution is purified by organic solvent extractions and in-situ converted in to atorvastatin calcium by reaction with aqueous solution of Ca++ such as calcium chloride, calcium acetate or calcium hydroxide, preferably calcium acetate, calcium chloride. The hemi-calcium salt of atorvastatin is in situ dissolved in an organic solvent by
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extraction, and then re-purified by aqueous extraction and treatment with activated carbon.
The organic solvent used at purification stage of atorvastatin sodium salt solution can be selected from dialkyl ethers like diethyl ether, methyl tert-butyl ether, diisopropyl ether, more preferably methyl tertbutyl ether. The solvents which can be used for insitu dissolution of atorvastatin hemi-calcium salt can be selected from a group of alkyl esters of relatively smaller carbon chain alcohols like methanol, ethanol, n-propanol, isopropanol, n-butanol etc and carboxylic acids like formic, acetic, propionic or butyric acids; methyl acetate, ethyl acetate, propyl acetate or mixtures thereof were found to be specifically more useful.
The solution of atorvastatin hemi-calcium salt in organic solvent, which has been purified earlier by extraction and treatment with active carbon, is dried over desiccant agents like anhydrous sodium sulphate or anhydrous magnesium sulphate and then molecular sieves. It is then subjected to the next stage of precipitation of the hemi-calcium salt. The solution of atorvastatin hemi-calcium salt in above mentioned esters can be pre-diluted with other solvents like tetrahydrofuran, or alcohols like isopropanol, ethanol and n-propanol in volume proportions of 5% to 40%, preferably 10% to 25%, before undertaking precipitation. The organic solvents which can be utilized for the precipitation process mainly include relatively less polar linear or cyclic hydrocarbons with C1 to C8 carbon atoms and mixtures thereof. Relatively more preferable hydrocarbons include pentane, hexane, heptane, cyclohexane methyl cyclohexane and toluene. The other group of solvents which can be used in amorphous precipitation include linear alkyl ethers R1-O-R2 with C1

to C4 carbons and the mixtures thereof as well as the mixtures of such ethers with the above mentioned hydrocarbons, in volume proportions ranging from 5% to 20%.
It has also been observed that use of certain pharmaceutically acceptable agents like polydimethyl siloxane (dimethione), simethicone (activated dimethicone), or other such silicones in low concentration such as 0.05% to 0.15% w/v w.r.t. the volume of precipitation solvent. Such silicone agents, seem to improve product characteristics like color and stability of the amorphous product. Stability data of amorphous atorvastatin calcium prepared as per this method was generated under accelerated stability conditions [Temperature 40°C, ±2°C, Relative humidity 75%, ±5%, period 3 months], and was compared with that of the sample prepared without addition of simethione. The fall in purity level for a sample prepared with simethicone addition was only 2.58% (Initial value 99.60%, after 3 months 97.02%), as compared to 3.38 % for the sample prepared without simethicone addition (Initial value, 99.65%, after 3 months 96.27%). Thus, rate of degradation of the product was found to be lesser by 0.8%. This is considered advantageous for the products stability characteristics and behavior. Siloxane polymers like dimethicone, simethicone etc being well established pharmaceutical agents and being practically inert, are considered acceptable for such use, especially at given low concentrations.
The process of amorphisation by mixing the solution of atorvastatin hemi-calcium salt with relatively lower polar solvents like hydrocarbons or ethers as described above, is carried out under inert atmosphere with nitrogen gas blanketing. The mixing is carried out preferably by gradual addition of
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atorvastatin hemi-calcium salt solution into the vessel containing lower polar solvent under mechanized agitation. The temperature of the mixture is maintained between 45°C to (-)65°C, preferably between 30°C to (-)50°C. The precipitated amorphous product is isolated by vacuum filtration under inert nitrogen gas atmosphere. The product cake is washed with the same low polar solvent containing the silicone agent and sucked dry to maximum extent. It is dried in vacuum at 30 - 55°C, preferably at 35°C - 45°C for several hours. The dried product is stored in sealed, low porosity containers under nitrogen cover at controlled temperature range of 2°C - 8°C.
The product atorvastatin hemi-calcium prepared as per above procedure is tested by power X-ray diffraction method and the diffractogram obtained clearly depicts complete amorphous character of the product (formula I and II).
The main advantages of the process of current invention are the following:
1. The method provides amorphous atorvastatin calcium of high purity and improved stability characteristics.
2. The process involves built in operations to enhance purity of the product, without any need of intermediate product isolation and separate purifications.
3. The process is characterized by specific operations which provide required environment necessary for purity and stability.
4. The method is fairly reproducible and can be easily scaled up to manufacturing level.
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The present invention will now be illustrated by the following examples, which are not intended to limit effective scope of the claims. As a consequence, any variations of the invention described above are not to be regarded as departure from the spirit and the scope of invention as claimed. The present envention has been described in terms of its specific embodiments, and for those skilled in the art various modifications, parallels and equivalents will be apparent and are intended to be included within the scope of present invention.
Example : 1
[R-(R*,R*)]-2(4-fluorophenyl)-β,δ-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-l-heptanoic acid hemi-calcium salt, (Formula I)
Preparation of atorvastatin hemi-calcium salt (formula I) solution is described as under:
Compound of formula II 15 gm (0.023 mole), was dissolved in 300 ml methanol, and 16 ml 2N aqueous HCl was added slowly at room temperature. The reaction mass was stirred at room temperature for 8 hrs while the reaction was monitored by TLC.
Aqueous 10% NaOH solution was added to the above solution at room temperature till pH 7 to 7.5. To this neutralized solution 300 mg active carbon was added, the solution was stirred for 30 minutes and then filtered through Celite bed. Filtrate was collected in a reaction vessel and then addition of second lot of aqueous 10% NaOH soln is started to increase pH up to 12 to 12.5 (approximately 35 ml alkali soln is consumed). The reaction mass is
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stirred for 8 to 10 hrs at room temperature while monitoring the reaction by TLC. After the reaction is over, the mass is filtered through Celite bed. The filtrate was concentrated under vacuum to around 90 ml and then 15 ml methanol, 45 ml water and 90 ml methyl-tert-butyl ether were added. The mass was stirred for 30 minutes and allowed to settle. The aqueous layer containing the product was separated and collected in a vessel. The organic layer was extracted with 25 ml water and the aqueous layer was pooled up with the main aqueous layer. The combined aqueous layer was washed with 20 ml methyl-tert-butyl-ether, and then neutralized with 2 N HCl to adjust pH up to 7.5 to 8.0 Then 150 ml ethyl acetate was added and stirred for 15 minutes, followed by addition of aqueous solution of 2.18 gm calcium acetate in 20 ml demineralised water. The reaction mass was stirred at 35°C - 40°C for 2 hrs and then cooled to 30°C. It was then allowed to settle and organic and aqueous layers were separated. The aqueous layer was again extracted twice with 50 ml ethyl acetate. The organic layers were combined and washed with 20 ml x 2 demineralised water. The organic layer containing atorvastatin hemi-calcium salt was separated. It was treated with 500 mg active carbon, stirred for 1 hr and filtered through Celite bed. Filtrate was dried over molecular sieve , re-filtered and then concentrated at 40°C to 45°C under vacuum, to 100 to 105 ml volume. It was used for the next stage of precipitation.
Example : 2
Pyrrole compound (of formula II) 15 gm (0.023 mole), was dissolved in 300 ml methanol, and 15.75 ml 2N aqueous HCl was added slowly at room temperature. The reaction mass was stirred at room temperature for 8 hrs while the reaction was monitored by TLC.
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Aqueous 10% NaOH solution was added to the above solution at room temperature till pH 7 to 7.5. To this neutralized solution 300 mg active carbon was added, the solution was stirred for 30 minutes and then filtered through Celite bed. Filtrate was collected in a reaction vessel and then addition of second lot of aqueous 10% NaOH soln is started to increase pH up to 12 to 12.5 (approximately 35 ml alkali soln is consumed). The reaction mass is stirred for 8 to 10 hrs at room temperature, while monitoring the reaction by TLC. After the reaction is over, the mass is filtered through Celite bed. The filtrate was concentrated under vacuum to around 90 ml and then, 15 ml methanol, 45 ml water and 90 ml methyl-tert-butyl ether was added. The mass was stirred for 30 minutes and allowed to settle. The aqueous layer containing the product was separated and collected in a vessel. The organic layer was extracted with 25 ml water and the aqueous layer was pooled up with the main aqueous layer. The combined aqueous layer was washed with 20 ml methyl tert butyl ether, and then neutralized with 2NaHCl to adjust pH upto 7.5 to 8.0 Then 150 ml ethyl acetate was added and stirred for 15 minutes, aqueous solution of 2.18 gm calcium acetate in 20 ml demineralised water. The reaction mass was stirred at 35 - 40°C for 2 hrs and then cooled to 30°C. It was then allowed to settle and organic and aqueous layers were separated. The aqueous layer was again extracted twice with 50 ml ethyl acetate. The organic layers were combined and washed with 20 ml x 2 demineralised water. The organic layer containing atorvastatin hemi-calcium salt was separated. It was treated with 500 mg active carbon stirred for 1 hr and filtered through Celite bed filter. Filtrate was dried over molecular sieve, re-filtered and then concentrated at 40°C to 45°C under vacuum to 80 ml volume. In this solution 20 ml tetrahydro furan was added and this mixed solution was used for the next stage of precipitation.
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Preparation of amorphous atorvastatin hemi-calcium salt (I)
Example : 3
Solution of atorvastatin hemi-calcium salt prepared as per example 1 is then drop-wise added to methyl cyclohexane (600ml) under mechanical stirring at ambient temperature (28°C - 30°C) under inert atmosphere with nitrogen gas. Addition is completed in about one hour. During the addition of atorvastatin hemi-calcium solution to methyl cyclohexane, precipitation of amorphous atorvastatin calcium salt begins. After completion of solution addition, the suspension is further stirred for 1 hour at room temperature.
The suspended product obtained was filtered and washed with 75ml methylcyclohexane. White product was dried in vacuum oven at 40°C-45°C for 12 hrs.
The product obtained was characterized as amorphous atorvastatin calcium based on its X-ray powder diffraction pattern. Yield 11.5 gms, HPLC purity- 99.64 %
Example -4
Solution of atorvastatin hemi-calcium salt prepared as per example 1 is then drop-wise added to methyl cyclohexane (600ml) containing 0.075% (w/v) of polydimethylsiloxane under mechanical stirring at room temperature and inert atmosphere with nitrogen gas. Addition continued for one hour. During addition of atorvastatin hemi-calcium solution to methyl cyclohexane the precipitation of amorphous atorvastatin calcium salt begins. After completion of solution addition, the suspension is further stirred for1 hour at room temperature.
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The product obtained was filtered, and wash by 75ml methylcyclohexane containing 0.075% (w/v) polydimethylsiloxane. The fine white product was dried in vacuum oven at 40°-45°C for 12 hrs.
The powdered material obtained was characterized as amorphous Atorvastatin calcium based on its X-ray powder diffraction pattern.
Yield 11.7 gms, HPLC purity- 99.65 %
Example -5
Solution of atorvastatin hemi-calcium salt prepared as per example 1 is then added slowly to methyl cyclohexane (600ml) containing 0.09% (w/v) simethicone under mechanical stirring at -60 °C under inert atmosphere with nitrogen gas. Addition takes around one hour. During addition of atorvastatin hemi-calcium solution to methyl cyclohexane the precipitation of amorphous atorvastatin calcium salt begins. After completion of solution addition, the suspension is further stirred at (-)50°C to (-)60°C and for 30 minutes at room temperature.
The product obtained was filtered and washed with 75ml methylcyclohexane containing 0.09% (w/v) simethicone. The fine white product was dried in vacuum oven at 40°-45°C for 12 hrs.
The powdered material obtained was characterized as amorphous Atorvastatin calcium based on its X-ray powder diffraction pattern.
Yield 11.8gm, HPLC purity- 99.65 %
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Example -6
Solution of atorvastatin hemi-calcium salt prepared as per example 1 is then drop-wise added to methyl cyclohexane 540ml and 60ml dry toluene containing 0.08% (w/v) polydimethylsiloxane under mechanical stirring at -60°C under inert atmosphere with nitrogen gas. Addition was completed in 40 minutes. The suspension of the amorphous product precipitated thus is further stirred for about one hour at (-)50°C to (-)60°C.
The product obtained was filtered rapidly and washed by chilled 75ml methylcyclohexane containing 0.08% (w/v) of polydimethylsiloxane. The fine white product was dried in vacuum oven at 40° - 45°C for 12 hrs.
The powdered material obtained was characterized as amorphous Atorvastatin calcium based on its X-ray powder diffraction pattern.
Yield 11.6gms, HPLC purity- 99.66 %
Example -7
Solution of atorvastatin hemi-calcium salt prepared as per example 1 is then dropwise added to a mixture of methyl cyclohexane 540ml and 60ml dry toluene containing 0.10% (w/v) simethicone under mechanical stirring at (-)40°C under inert atmosphere with nitrogen gas. Addition takes around 1 hr. During addition of Atorvastatin hemi-calcium solution to methyl cyclohexane the precipitation of amorphous Atorvastatin calcium salt begins. After completion of solution addition, the suspension was further stirred for 1 hour at (-)30°C to (-)40°C.
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The product obtained was rapidly filtered and washed by chilled 75 ml methylcyclohexane containing 0.10% (w/v) simethicone. The fine white product was dried in vacuum oven at 40° - 45°C for 12 hrs.
The powdered material obtained was characterized as amorphous Atorvastatin calcium based on its X-ray powder diffraction pattern.
Yield 11.7gm, HPLC purity- 99.61 %
Example -8
Solution of atorvastatin hemi-calcium salt prepared as per example 1 is then drop-wise added to heptane 540ml and 60ml dry toluene containing 0.05% (w/v) polydimethylsiloxane under continued mechanical stirring at (-)40 °C under inert atmosphere with nitrogen gas. During addition of atorvastatin hemi-calcium, the precipitation of amorphous atorvastatin calcium salt begins. After completion of solution addition, the suspension is further stirred for 1 hour. The solvent was removed under stirring by vacuum distillation at ambient temperature under continued mechanical agitation.
The fine white product obtained was dried in vacuum oven at 40° - 45°C for 12 to 14 hrs.
The powdered material obtained was characterized as amorphous Atorvastatin calcium based on its X-ray powder diffraction pattern.
Yield 11.9gm, HPLC purity- 99.32 %
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Example -9
Solution of atorvastatin hemi-calcium salt prepared as example 2 is then drop-wise added to 700 ml dry cyclohexane, under very efficient mechanical stirring at 0 to 5°C in inert atmosphere with nitrogen gas. During addition of atorvastatin hemi-calcium solution to cyclohexane, the precipitation of amorphous Atorvastatin calcium salt starts developing rapidly. After completion of solution addition, the suspension is further stirred for 1 hour.
The product obtained was filtered, and washed with 75ml cyclohexane. The fine white product was dried in vacuum oven at 40 - 45°C for 10-12 hrs.
The powdered material obtained was characterized as amorphous atorvastatin calcium based on its X-ray powder diffraction pattern.
Yield 11.1 gm, HPLC purity- 99.57 %.
Example -10
Solution of atorvastatin hemi-calcium salt prepared as per example 2 is then dropwise added to 700ml dry petroleum ether (60 - 80°C), with continued mechanical stirring at room temperature under inert atmosphere with nitrogen gas. Addition takes about 1 hr. During addition of atorvastatin hemi-calcium solution to petroleum ether, the precipitations of amorphous atorvastatin calcium salt begins. After completion of addition of solution, the suspension further stirred for 1 hour at room temperature.
The product obtained was filtered and washed with 75ml petroleum ether. The fine white product was dried in vacuum oven at 40°-45°C for 10 - 12 hrs.
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The powdered material obtained was characterized as amorphous Atorvastatin calcium based on its X-ray powder diffraction pattern.
Yield 13.8gms, HPLC purity- 99.51 %
Example 11
Procedure for preparation of the pyrrole derivative (4R-Cis)-1,1-Dimethylethyl-6-[2[2-(4-fluorophenyl-5-(l-methylethyn-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrol-1 -yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate (II)
In a reaction flask was added tetrahderofuran 200 ml, toluene 200 ml and n-heptane 800 ml. To this mixture of solvents is added ± (4-fluoro-alpha-(2-methyl-1 -oxopropy l)-gama-oxo-N-beta-diphenyl benzenebutaneamine of formula 111(148 gms, 0.36 mole), (4R-Cis)-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxane-4-acetate (100 gms, 0.37 mole) of formula IV, pivalic acid 26 gms, and was heated to reflux for 40 hrs with azeotropic distillation arrangement to continuously remove the water produced during the reaction. The reaction mass was then cooled to ambient temperature and washed with saturated solution of sodium bicarbonate till pH 6.5 to 7.0. The organic layer is isolated and is treated with activated carbon (5 gms). The solvent is distilled off under vacuum, and resultant residue was dissolved in 400 ml isopropyl alcohol and cooled to room temperature. To the above solution 100 ml demineralised water was slowly added. The precipitated product was then cooled to 20°C, stirred and filtered. It is washed several times with 80% aqueous isopropanol. The product was dried at 40 - 45°C in a
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vacuum oven to give 165 gms of the title compound, which is next purified by recrystallisation from isopropanol and water.

Dated this 16th day of October, 2006.

MOHAM DEWAN
OF R.K.DEWAN & COMPANY
APPLICANTS' PATENT ATTORNEY

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