FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
"A PROCESS FOR THE PREPARATION OF AMORPHOUS ROSUVASTATIN
CALCIUM"
Glenmark Generics Limited an Indian Company, registered under the Indian company's Act 1957 and having its
registered office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099
The following specification describes the nature of the invention.

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of amorphous rosuvastatin calcium.
BACKGROUND OF THE INVENTION
Rosuvastatin calcium is a synthetic lipid-lowering agent, which acts by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Rosuvastatin calcium is chemically known as bis [(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-N-[methyl-N-(methylsulfonyl) amino] pyrimidin-5-yl]-(3R, 5S)-3, 5-dihydroxy hept-6-enoic acid] calcium salt, and represented by formula (I):

Rosuvastatin calcium is commercially available under the brand name CRESTOR™ as tablets containing 5mg, lOmg, 20mg or 40 mg of active ingredient.
United States Re-issue Patent No. RE 37314E describes a process for the preparation of rosuvastatin by reacting 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-pyrimidinecarbaldehyde with methyl (3R)-3-(tert-butyldimethyl -silyloxy)-5-oxo-6-triphenylphosphoranylidene hexanate in acetonitrile under reflux. The silyl group is then cleaved with hydrogen fluoride, followed by reduction with sodium borohydride (NaBIrU) and diethylmethoxyborane in tetrahydrofuran (THF) to obtain a methyl ester of rosuvastatin. The ester is then hydrolyzed with sodium hydroxide in ethanol at room temperature, followed by the removal of ethanol and the addition of ether to obtain the sodium salt of rosuvastatin. The sodium salt is then converted to the calcium salt by dissolving the sodium salt in water under a nitrogen atmosphere. An aqueous

solution of calcium chloride is then added dropwise to the solution at room temperature, stirring of reaction mixture, resulting in precipitation of rosuvastatin calcium.
United States Patent No. 7,511,140 describes processes for the preparation of rosuvastatin calcium by the addition of calcium chloride solution with water soluble salt of rosuvastatin at a temperature of 30°C to 45°C.
PCT Patent Publications WO2005/040134, WO2005/021511, WO2006/035277, WO2006/136407, WO2006/136408, and WO2007/099561 also disclose processes for the preparation of amorphous rosuvastatin calcium.
It is well established that the amorphous state is thermodynamically the form with the highest solubility. Consequently, amorphous forms exhibit a greater solubility in a solvent than any crystalline form. The increased solubility of amorphous actives, particularly in the pharmaceutical field, can lead to dramatically increased intrinsic dissolution rates when compared to crystalline forms.
For a drug to dissolve, its surface has first to be wetted by the surrounding fluid. Amorphous forms possess a chemically randomized surface which expresses equal amounts of hydrophobic and hydrophilic interactions which can lead to improved wettability expressed by a lower contact angle of the drug particle surface with a liquid. A lower contact angle represents a higher degree of hydrophilicity with consequently faster surface wetting and faster dissolution.
It has been disclosed in the art that the amorphous form advantageously exhibit high surface area that results to an increase in the solubility profile of the drug substance and in some cases different bio-availability pattern compared to the crystalline form (Konno T„ Chem. Pharm. Bull., 38, 2003 (1990)).
Batch variation in amorphous form makes it difficult to reproduce drug dissolution profiles and possibly absorption from batch to batch.
The present invention provides a process for the preparation of amorphous rosuvastatin calcium, which is consistently amorphous and is not contaminated with crystalline form, where the temperature at which the reaction of source of calcium with the water soluble salt of rosuvastatin is carried out is critical. Contrary to the present invention, consistently amorphous form of rosuvastatin calcium was not observed by the reaction of addition of calcium source to water soluble salt of rosuvastatin at a

temperature above 10 C, and the product was contaminated with crystalline form. Specifically the degree of crystallinity in the amoiphous rosuvastatin obtained was more than 5% (comparative example). Further, the product, which was in the form of lumps, had a higher extent of water entrapped in it, thus requiring increased drying time for water removal.
Surprisingly, the present invention provides the addition of a calcium source to a water soluble salt of rosuvastatin in an aqueous medium in the temperature range of about

00 C to about 100C, and further maintaining the temperature in the same range offers significant advantages in obtaining pure amorphous rosuvastatin calcium with good yield and high purity which is not contaminated with crystalline form. Advantageously, the present invention provides an amorphous rosuvastatin calcium with high polymorphic purity free of crystalline form.
The amorphous rosuvastatin calcium obtained by process of present invention has a degree of crystallinity less than about 5%, preferably less than 1%, more preferably less than 0.5%, and most preferably free of crystalline forms of rosuvastatin calcium.
The amorphous rosuvastatin calcium obtained by process of present invention does not precipitate out as aggregates and does not therefore have water/solvent entrapped in it and is easy to handle.
The amorphous rosuvastatin calcium obtained by the process disclosed herein is stable, consistently reproducible, and is particularly suitable for bulk preparation and handling. The amorphous rosuvastatin calcium obtained by the process disclosed herein is suitable for formulating rosuvastatin calcium.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of amorphous rosuvastatin calcium having a degree of crystallinity less than about 5%, comprising:
a) generating a water soluble salt of rosuvastatin in aqueous reaction mixture;
b) cooling the aqueous reaction mixture of water soluble salt of rosuvastatin at a
temperature of about 0 C to about 10 C;
c) adding a source of calcium to the reaction mixture obtained in (b) at a temperature of
about 0°C to about 10°C;

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d) stirring the aqueous reaction mixture at a temperature of about 0 C to about 10C; and
e) isolating the amorphous rosuvastatin calcium.
The present invention provides a pharmaceutical composition comprising amorphous rosuvastatin calcium obtained by the processes of the present invention and at least a pharmaceutically acceptable carrier.
DESCRIPTION OF THE INVENTION
The present invention is directed to an effective process for the synthesis of amorphous rosuvastatin calcium, having a degree of crystallinity less than about 5%.
In one embodiment, the present invention provides a process for the preparation of amorphous rosuvastatin calcium having a degree of crystallinity less than about 5%, the process comprising:
a) generating a water soluble salt of rosuvastatin in aqueous reaction mixture;
b) cooling the aqueous reaction mixture of water soluble salt of rosuvastatin at a
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temperature of about 0 C to about 1OC;
c) adding a source of calcium to reaction mixture obtained in step (b) at a temperature of about 0°C to about 10°C;
d) stirring the aqueous reaction mixture at a temperature of about 0 °C to about 10 °C; and
e) isolating the amorphous rosuvastatin calcium from the reaction mixture.
The suitable water soluble salt of rosuvastatin may be metal salt, for example an alkali metal salt like sodium, potassium or lithium. Preferably, the water soluble salt of rosuvastatin is a rosuvastatin sodium salt.
The water soluble salt of rosuvastatin may be generated in an aqueous reaction mixture. The aqueous reaction mixture may be water alone or water in combination with water miscible organic solvent. Preferably, it is water.
Suitable water miscible organic solvents include one or more of water miscible lower alcohols such as methanol, ethanol, isopropanol, and n-propanol; water miscible polar aprotic solvents, such as tetrahydrofuran, acetonitrile, 1,4-dioxane, N,N-dimethylacetamide and dimethylsulfoxide, mixtures thereof and the like.

The water soluble salt of rosuvastatin may be present as a solution or suspension in aqueous reaction mixture. Preferably, it is in solution.
In one embodiment, the water soluble salt of rosuvastatin may be generated by reacting rosuvastatin amine salts with an alkali base in water to form an aqueous reaction mixture.
Rosuvastatin amine salts include, but are not limited to rosuvastatin methyl amine, rosuvastatin ethyl amine, rosuvastatin isopropyl amine, rosuvastatin tert-butyl amine and the like. Preferably, the amine salt is rosuvastatin tert-butyl amine.
The alkali bases include, but are not limited to NaOH, LiOH, and KOH. The preferred base is NaOH.
The temperatures for carrying out the reaction in a) can be from about 15°C to about 50°C. Preferably, from about 25°C to about 30°C. More preferably, from about 20°Cto25°C.
The time required for the completion of reaction in a) can be from about 20 minutes to about 3 hours. Preferably from about 30 minutes to about 1 hour.
In one embodiment, the sodium salt of rosuvastatin may be generated by reacting rosuvastatin tert-butyl amine salt with sodium hydroxide in an aqueous medium to form sodium salt of rosuvastatin which may be in solution or optionally isolated if required.
In one embodiment, the water soluble salt of rosuvastatin may be generated by reacting rosuvastatin acid with an alkali base in the presence of water to form a solution of rosuvastatin salt.
In one embodiment, the water soluble salt of rosuvastatin may be prepared by reacting C1-C6 alkyl ester of rosuvastatin with an alkali base in the presence of water to form a solution of rosuvastatin salt.
The Cl-Ce alkyl ester of rosuvastatin may include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl and the like. Preferably, methyl or tert-butyl ester of rosuvastatin.
The alkali bases include, but are not limited to sodium hydroxide, lithium hydroxide, and potassium hydroxide. The preferred base is sodium hydroxide

The term "rosuvastatin acid" means (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoic acid.
In b) of the process just described above, the aqueous reaction mixture of water soluble salt of rosuvastatin obtained after step a) is cooled to about 0°C to about 100C.
In one embodiment, in b) the sodium salt of rosuvastatin obtained after a) of the

process just described above, is cooled to about 00 C to about 100C.
In c) of the process just described above, a source of calcium is added to the cooled aqueous reaction mixture obtained in (b) at a temperature in the range of about 0°C to about 10°C, preferably about 5°C to about 9°C.
The source of calcium includes, but is not limited to calcium chloride dihydrate, calcium acetate and the like. Preferably, calcium chloride dihydrate.
In general, the solution of calcium chloride will be an aqueous solution or substantially an aqueous solution. The addition to the reaction mixture is carried out slowly.
In one embodiment in c) of the process just described above, aqueous calcium chloride dihydrate is added to the cooled aqueous reaction mixture of rosuvastatin sodium

salt obtained in (b) at a temperature in the range of about 00 C to about 100 C. Preferably the addition is carried out in the temperature rang of about 5 C to about 9 C.
In d) of the process just described above, the aqueous reaction mixture obtained is

stirred at a temperature in the range of about 0-100 C. Stirring may be carried out for about 2 hours to about 3 hours.
In one embodiment, in d) the aqueous reaction mixture, which is obtained after addition of aqueous calcium chloride dihydrate to the cooled aqueous reaction mixture of

rosuvastatin sodium salt, is stirred at a temperature in the range of about 0-100 C for a period of about 2 hours.
In e) of the process just described above, the amorphous rosuvastatin calcium is isolated.
In one embodiment, the present invention provides the isolation process of the amorphous rosuvastatin calcium, in the process described above, from the reaction mixture of d), the process comprising:

(a) subjecting the reaction mixture of (d) to filtration to obtain a solid;
(b) optionally washing the solid with water; and
o
(c) stirring the solid with water at a temperature of 00 C to1OC
In one embodiment, the solid obtained after filtration is subjected to washing with
o
water at a temperature of 0-10 C.
In one embodiment, the solid obtained after water washing may be stirred with water at a temperature of about 0-100 C, followed by filtration to obtain amorphous rosuvastatin calcium. Optionally, if required, this process may be repeated.
In one embodiment, the present invention provides a process for the preparation of amorphous rosuvastatin calcium having a degree of crystallinity less than about 5%, consisting:
a) generating a water soluble salt of rosuvastatin in aqueous reaction mixture;
b) cooling the aqueous reaction mixture of water soluble salt of rosuvastatin at a
o o
temperature of about 0 C to about 10 C;
c) adding a source of calcium to reaction mixture obtained in (b) at a temperature of
about 0°C to about 10°C;
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d) stirring the aqueous reaction mixture at a temperature of about 0 C to about 1OC; and
e) isolating the amorphous rosuvastatin calcium.
The amorphous rosuvastatin calcium obtained by process of present invention has a degree of crystallinity less than 5%, preferably less than 1%, more preferably less than 0.5%, and most preferably free of crystalline forms of rosuvastatin calcium, as measured by X-ray powder diffraction (XRPD).
In one embodiment, present invention provides amorphous rosuvastatin calcium having a degree of crystallinity less than about 5%, as measured by X-ray powder diffraction.
In one embodiment, present invention provides amorphous rosuvastatin calcium having a degree of crystallinity less than about 3%, as measured by X-ray powder diffraction.
In one embodiment, present invention provides amorphous rosuvastatin calcium having a degree of crystallinity less than about 2%, as measured by X-ray powder diffraction

In one embodiment, present invention provides amorphous rosuvastatin calcium having a degree of crystallinity less than about 1%, as measured by X-ray powder diffraction.
In one embodiment, present invention provides amorphous rosuvastatin calcium having a degree of crystallinity less than about 0.5%, as measured by X-ray powder diffraction.
In one embodiment, present invention provides amorphous rosuvastatin calcium free of crystalline forms of rosuvastatin calcium, as measured by X-ray powder diffraction.
The % crystallinity of the obtained product was measured with PXRD (Powder X-ray Diffraction) as described below:
A thin layer of the triturated sample was smeared onto a cut silicon single crystal zero background holder which was rotated during the measurement. CuKa radiation and constant or automatic antiscatter and divergence slits were used to obtain a diffractogram froml or2°20toatleast35°.
The % crystallinity was calculated with the formula: % crystallinity = 100*C / (A+C) C= the area from the peaks in the diffractogram ("the crystalline area"), A= the area between the peaks and the background ("the amorphous area").
Area calculations were performed between 4-33 20. The lowest intensity value found in this interval was chosen as the constant background and substrated from the area A. When constant slits were used the increased background at low angles due to the influence from the primary beam was also subtracted from the area A. The crystallinity was measured to be 80+5% (calculated interval 4-33°)
The degree of crystallinity of the obtained product can be measured with techniques known in the art. Illustratively, WO 97/41114 describes an analytical technique using powder X-ray diffraction (PXRD), herein incorporated as reference in its entirety.
In one embodiment, the present invention provides rosuvastatin calcium obtained by the processes herein described, having chemical purity more than about 99.8% as measured by high performance liquid chromatography (HPLC).

The starting compound rosuvastatin tert-butyl amine salt may be prepared by any method known in the art.
In another embodiment, the present invention provides a pharmaceutical composition comprising amorphous rosuvastatin calcium as disclosed herein and one or more pharmaceutically acceptable excipients.
In another embodiment, the present invention provides a pharmaceutical composition comprising amorphous rosuvastatin calcium made by processes disclosed herein, and one or more pharmaceutically acceptable excipients.
In another embodiment, the present invention provides a process for preparing a pharmaceutical formulation comprising combining amorphous rosuvastatin calcium with one or more pharmaceutically acceptable excipients.
In another embodiment, the present invention provides a method of administering the pharmaceutical composition of present invention in a standard manner. For example, the modes of administration may include oral or parenteral administration, using conventional systemic dosage forms, such as a tablets, capsules, pills, powders, aqueous or oily solutions or suspensions, emulsions, sterile injectable. The dosage forms will include the necessary carrier material, excipient, lubricant, buffer, bulking agent, antioxidant, dispersant or the like. In particular, compositions for oral administration are preferred.
The processes, herein described, for the preparation of rosuvastatin and its pharmaceutically acceptable salt are simple, eco-friendly, inexpensive, reproducible, robust and well suited on industrial scale.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

COMPARATIVE EXAMPLE 1
In purified water (6.0 lit), nitrogen gas was purged at about 70-80 C for about 2-3 hours
and cooled to about 25-30°C under nitrogen purging and then used for reaction.
The mixture of rosuvastatin tert-butyl amine (64gm) and purified water (640ml) was
o o
stirred under nitrogen purging at about 25-30 C and then cooled to about 20-25 C. Sodium hydroxide solution (prepared by dissolving 4.85gm of NaOH in 256ml of
o
purified water under nitrogen purging at about 20-25 C) was added to stirred mixture for, about 20-25 C for about 20-30 minutes and stirring was continued for about one hour at about the same temperature. Purified water (256ml) v/as distilled out under vacuum below about 40 C. The reaction mixture was cooled to about 20-25 C, filter and washed
o
with purified water and obtained reaction mass was further cooled to about 10-15 C. Solution of calcium chloride dihydrate (prepared by dissolving 10.65 gm of CaCh dihydrate (AR Garde) into 192 ml of purified water) was added at about 10-15 C for about 20-30 minutes and mixture was stirred at same temperature for about 2 to 3 hours, then filtered and washed with purified water. Purified water (320ml) was added to the obtained wet material at about 20-25 C, cool the reaction mixture at about 10-15 C and stirred the reaction mixture at same temperature for about 20-30 minutes. The reaction mass was filtered, washed with purified water (2x160ml) and further purified water (320ml) was added to wet material. The reaction mass was cooled to about 10-15 C and stirred at about the same temperature for about 20-30 minutes, the resulting reaction mass was filtered, washed with purified water and dried under vacuum at about 40 - 45 C to obtain the title product. Degree of crystallinity is ~ 5.9%.
COMPARATIVE EXAMPLE 2
In purified water (6.0 lit), nitrogen gas was purged at about 70-80 C for about 2-3 hours
and cooled to about 25-30 C under nitrogen purging and then used for reaction,
The mixture of rosuvastatin tert-butyl amine (64gm) and purified water (640ml) was
o o
stirred under nitrogen purging at about 25-30 C and then cooled to about 20-25 C. Sodium hydroxide solution (prepared by dissolving 4.85gm of NaOH in 256ml of
o
purified water under nitrogen purging at about 20-25 C) was added to stirred mixture for

about 20-25C for about 20-30 minutes and stirring was continued for about one hour at about the same temperature. Purified water (256ml) was distilled out under vacuum below about 40 C. The reaction mixture was cooled to about 20-25 C, filter and washed with purified water and obtained reaction mass was maintained at 20-25 C. Solution of calcium chloride dihydrate (prepared by dissolving 10.65 gm of CaCl2 dihydrate (AR Grade) into 192 ml of purified water) was added at about 20-25 C for about 20-30 minutes and mixture was stirred at same temperature for about 2 to 3 hours, then filtered and washed with purified water. Purified water (320ml) was added to obtained wet material at about 20-25 C, and stirred the reaction mixture at same temperature for about 20-30 minutes. The reaction mass was filtered, washed with purified water (2x160ml) and further purified water (320ml) was added to wet material. The reaction mass was cooled to about 20-25 C and stirred at same temperature for about 20-30 minutes, the resulting reaction mass was filtered, washed with purified water and dried under vacuum at about 40-45 C to obtain the title product. Degree of crystallinity is ~ 8.29%.
EXAMPLE 1
Preparation of amorphous rosuvastatin calcium from tert-butyl amine salt of rosuvastatin
In purified water (6.0 lit), nitrogen gas was purged at about 70-80 C for about 2-3 hours and cooled to about 25-30 C under nitrogen purging and then used for reaction. The mixture of rosuvastatin tert-butyl amine (64gm) and purified water (640ml) was stirred at about 25-30 C and then cooled to about 20-25 C. Sodium hydroxide solution (prepared by dissolving 4.85gm of NaOH in 256ml of purified water under nitrogen purging at about 20-25 C) was added to stirred mixture for about 20-25 C for about 20-30minutes and stirring was continued for about one hour at about the same temperature.
o
Purified water (256ml) was distilled out under vacuum below about 40 C. The reaction mixture was cooled to about 20-25 C, filtered and washed with purified water and obtained reaction mass was further cooled to about 0-10 C. Solution of calcium chloride dihydrate (prepared by dissolving 10.65 gm of CaCl2 dihydrate (AR Garde) into 192 ml of purified water) was added slowly at about 0-100C for about 20-30 minutes, and

reaction mixture was stirred at same temperature for about 2-3 hours, filtered and washed with purified water, then suck dry material for about 5-10 minutes. Purified water (320ml) was added to obtained wet material, cool at about 0-10 C and reaction mixture was stirred at about 0-5 C for about 20-30 minutes. The reaction mixture was filtered, washed with water (2x160ml) then suck the dry material for about 5-10 minutes. Purified water (320 ml) was added to wet material and cool at about 0-10 C and the reaction mixture was stirred at same temperature for about 20-30 minutes. The resulting reaction
o
mass was filtered, washed with purified water and dried under vacuum at about 40 - 45 C to obtain the title product. (No crystallinity observed)

The present invention is particularly described below:
A] A process for the preparation of amorphous rosuvastatin calcium having a degree of
crystallinity less than about 5%, comprising:
a) generating a water soluble salt of rosuvastatin in aqueous reaction mixture;
b) cooling the aqueous reaction mixture of water soluble salt of rosuvastatin at a temperature of about 0 C to about 1O0C;
c) adding a source of calcium to reaction mixture obtained in (b) at a temperature of about 0°C to about 10°C;
d) stirring the aqueous reaction mixture at a temperature of about 0 C to about 1O0C; and
e) isolating the amorphous rosuvastatin calcium from the reaction mixture.

B] The process as defined in A, wherein the water soluble salt of rosuvastatin is a sodium salt.
C] A process as defined in A, wherein the source of calcium is calcium chloride dihydrate.
D] A process as defined in A, wherein the amorphous rosuvastatin calcium is isolated from the reaction mixture by process steps comprising:

(a) subjecting the reaction mixture of step (d) to filtration to obtain a solid;
(b) optionally washing the solid with water; and
(c) stirring the solid with water at a temperature of about 0 C to about 1O0C
E] Amorphous rosuvastatin calcium having a degree of crystallinity less than about 5%.