Indian Patents. 260931:PROCESS FOR PREPARING AMORPHOUS FROM OF ROSUVASTATIN CALCIUM

Title of Invention	PROCESS FOR PREPARING AMORPHOUS FROM OF ROSUVASTATIN CALCIUM
Abstract	This invention relates to the preparation of amorphous form of Rosuvastatin Calcium.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & The Patent Rules, 2003 COMPLETE SPECIFICATION (See se et ion 10 and mie 13) TITLE OF THE INVENTION "PROCESS FOR PREPARING AMORPHOUS FORM OF ROSUVASTATIN CALCIUM" We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Roads, Ahemdabad 380 015, Gujarat, India. Thefollowing specification particularty describes the invention and the manner in which it is to be performed. Process for preparing amorphous form of Rosuvastatin Calcium Background of invention: Rosuvastatin Calcium (III) is a synthetic lïpid-lowering agent. Rosuvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. The statins are used to reduce blood cholesterol levels of patients in need of such treatment. The Rosuvastatin is also known as "Superstatin" with potent cholesterol lowering action and it is chemically known as (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl) amino]pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium salt, having the structural formula III. The patent EP 0521471 discloses the conversion of the sodium salt of Rosuvastatin into the calcium salt and the patent also discloses that the calcium salt of Rosuvastatin obtained was amorphous form. The patent WO 01/60804 Al as well as US 2003/0045718 Al disclose preparation of different crystalline salts of Rosuvastatin such as, lithium, magnesium, ammonium, alkyl ammonium salts etc. More recently published US Patent 6589959 discloses the crystalline Form-A, comprising the crystallization of an amorphous form of Rosuvastatin calcium from methanol and acetonitrile. Disclosure of invention: There can be many advantages using the amorphous form of a drug; most important are enhanced solubility and bioavailabiUty. The present invention describes a simplified and one pot manufacturing of amorphous Rosuvastatin calcium, comprising the hydrolysis of protected diol i.e. tert-butyl [(4S,6R)-6-((E)-2-{4-( 4-fluorophenyl)-6-isopropyl-2- 2 [methyl (methylsulfonyl)araino]-5-pyrimidinyl}ethenyl)-2,2-dimethyl-l,3-dioxan-4- yl]acetate (I) with IN hydrochloric acid in diluted aqueous methanol. The hydrolyzed mass is then subjected to the treatment of dilüte aqueous solution of sodium hydroxide and pH of the solution is adjusted to 7.0 to 7.5 after complete conversion to its corresponding sodium salt. The solution thus obtained is charcoalized and filtered over hyflosupercell bed as well as through 5μ filter-pads providing the clear solution. The clear solution is then reduced to 85% of volume by distilling-off the filtrate under reduced pressure below 50°C and the solution of reduced volume is again filtered through 5μ filter-pads. The clear solution thus obtained is treated with a dilute aqueous solution of calcium chloride to precipitate Rosuvastatin calcium as a white solid. Wet cake of Rosuvastatin calcium thus obtained is then filtered and dried under vacuüm at 45°C to 50°C to afford dry amorphous Rosuvastatin calcium (III). This process is a one-pot synthesis (Scheme-1) wherein the sodium salt of Rosuvastatin (II) is not isolated. The X-ray powder difïractogram confirms the amorphous property of Rosuvastatin calcium. 3 Scheme-1 Description of the drawings accompanying the provisional speciflcation: Fig 1. shows X-ray powder diffractogram of Rosuvastatin calcium obtained in accordance with the present invention. It has an amorphous form, which is confirmed by its X-ray powder diffractogram (Figure-1). The present invention will be more fully understood from the example given below, but do not exemplify the fbll scope of the invention. Example: l Hydrolysis ofprotected diol (I) 8.0 kg (13.85 mole) of tert-butyl [(4S,6R)-6-((E)-2-{4-(4-fluorophenyl)-6-isopropyl-2- [methyl (methylsulfonyl) amino]-5-pyrimidinyl} ethenyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate (I) is added into 200 L of methanol under stirring at 25°C to 35°C and reaction mass is cooled to 5°C to 10°C. 19.2 L (19.18 mole) of 1.0 N HC1 is added into the reaction mass under stirring within 30 minutes by maintaining 5°C to 10°C temperature. The temperature of the reaction is raised to 30°C to 35°C and it is maintained under stirring for 30 minutes. The reaction is analyzed on thin layer chromatography and when hydrolysis is completed, the reaction mass is allowed to cool 5°C to 10°C. Example: 2 Sodium saltformation to obtain compound (IT) Into the above-hydrolyzed mass, 26.4 L of 10% sodium hydroxide solution (66.0 mole) is added under stirring within 30 minutes at 5°C to 10°C, 24.0 L of process water is also added in the reaction mass within 30 minutes by maintaining 5°C to 10°C, the resulting solution is stirred for 15 more minutes by maintaining the same temperature. Slowly temperature of the reaction mass is raised to 20°C to 25°C and stirred for 30 minutes. The reaction solution is analyzed on thin layer chromatography and when the sodium salt formation is completed; pH of reaction mass is adjusted to 7.0 - 7.5 by adding IN HC1. The dear solution thus obtained is treated with 0.4 kg of activated charcoal followed by filtration through hyflosupercell bed and 5μ filter-pads with washing of 4.0 L of methanol. 4 Example: 3 Rosuvastatin calcium dry amorphous form (III) The above filtrate is concentrated to it's 50% of volume by distillation under reduced pressure, below 50°C temperature till it affords approximately 125 L of the reaction solution. Two 80 L toluene washings were provided to the solution and again the reaction solution is reduced to 50%, by distillation under vacuüm, below 50°C, Concentrated solution thus obtained is allowed to cool at 20°C to 30°C. The entire volume of concentrated solution is filtered through 5μ filter-pads followed by two 4.0 L washings of process water. The filtered solution is cooled to 5°C to 10°C and a freshly prepared aqueous calcium chloride solution (1.92 kg Calcium chloride (17.3 mole) in 8.0 L of process water) is added into it within 30 minutes maintaining the same temperature. Temperature of the reaction mass is then raised to 20°C to 30°C to afford the solid product. Product thus obtained is centrifuged, spin dried and wet cake is finally dried under vacuüm at 45°C to 50°C to afford 6.5 kg of dry calcium sak of (3S,5R,6E)-7-{4-(4-fIuorophenyl)- 6-isopropyl-2-[methyl(methyl sulfonyl) amino]-5-pyrimidinyl}-3,5-dihydroxy-6- heptenoate i. e. Rosuvastatin Calcium. The amorphous form of Rosuvastatin Calcium obtained is having purity 99.40 % (HPLC) and water content 2.75% (w/w). Rosuvastatin calcium thus obtained is having amorphous form, which is confirmed by its X-ray powder diffractogram (Figure-1). 5 We claim: 1. One pot process of manufacturing of amorphous Rosuvastatin Calcium comprising the steps of (a) hydrolysis of the protected diol, (tertiary-butyl [(4S,6R)-6-((E)-2-{4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5- pyrimidinyl}ethenyl)-2)2-dimethyl-l)3-dioxan-4-yl]acetate) with 1.0 N hydrochloric acid in aqueous methanol. (b) conversion of the diol ((E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl) amino]pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6- enoic acid) to corresppnding sodium salt with suitable base in suitable solvent combination. (c) treatment of the solution of sodium salt with Calcium chloride solution to obtain the amorphous form of Rosuvastatin Calcium salt ((E)-7-[4-(4-fluorophenyl)-6- isopropyl-2-[methyl(methylsulfonyl) amïno] pyrimidin-5-yl] (3R,5S)-3,5- dihydroxyhept-6-enoic acid calcium salt). 2. The process as.claimed claim l wherein in step (a) mmeral acid is used for the hydrolysis of protected diol. 3. The process as claimed claim l wherein in step (a) the mineral acid used for hydrolysis, is preferably dilute hydrochloric acid of 1.0 N concentration. 4. The process as claimed claim l wherein in step (a) the mole ratio of protected diol to Hydrochloric acid used is 1: 1.5, most preferably 1:1.38. 5. The as claimed in claim l wherein in step (a) the temperature maintained during hydrolysis process of Rosuvastatin protected diol is in the range 0-35°C. 6. The process as claimed claim l wherein in step (a) the temperature maintained during addition of 1.0 N Hydrochloric acid is preferably 5°C to 10°C. 7. The process as claimed claim l wherein in step (a) the pH is adjusted to 7.0 - 7.5 by adding l .0 N Hydrochloric acid, after the formation sodium salt. 6 7 8. The process as claimed claim l wherein the solvent used is aqueous alcohol of C-1 to C-4, more preferably methanol. 9. The process as claimed claim l wherein in step (c) said sodium salt filtrate is concentrated to its 50 % volume under reduced pressure. 10. The process as claimed claim l wherein in step (c) the concentrated solution is cooled to IO°C to 30°C preferably 20°C to 30°C. 11. The process as claimed claim l wherein in step (c) the mole ratio of Rosuvastatin protected diol to calcium chloride is 1:1.25. 12. The process as claimed claim l wherein in step (c) solution is further cooled to 0°C to 10°C preferably to 5°C to 10°C to precipitate Calcium salt of Rosuvastatin.

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See se et ion 10 and mie 13)
TITLE OF THE INVENTION
"PROCESS FOR PREPARING AMORPHOUS FORM OF
ROSUVASTATIN CALCIUM"
We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act,
1956, of Zydus Tower, Satellite Cross Roads, Ahemdabad 380 015, Gujarat, India.

Thefollowing specification particularty describes the invention and the manner in which it is
to be performed.

Process for preparing amorphous form of Rosuvastatin Calcium
Background of invention:
Rosuvastatin Calcium (III) is a synthetic lïpid-lowering agent. Rosuvastatin is an inhibitor
of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. The statins are used
to reduce blood cholesterol levels of patients in need of such treatment. The Rosuvastatin
is also known as "Superstatin" with potent cholesterol lowering action and it is chemically
known as (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)
amino]pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium salt, having the
structural formula III.

The patent EP 0521471 discloses the conversion of the sodium salt of Rosuvastatin into
the calcium salt and the patent also discloses that the calcium salt of Rosuvastatin obtained
was amorphous form. The patent WO 01/60804 Al as well as US 2003/0045718 Al
disclose preparation of different crystalline salts of Rosuvastatin such as, lithium,
magnesium, ammonium, alkyl ammonium salts etc.
More recently published US Patent 6589959 discloses the crystalline Form-A, comprising
the crystallization of an amorphous form of Rosuvastatin calcium from methanol and
acetonitrile.
Disclosure of invention:
There can be many advantages using the amorphous form of a drug; most important are
enhanced solubility and bioavailabiUty. The present invention describes a simplified and
one pot manufacturing of amorphous Rosuvastatin calcium, comprising the hydrolysis of
protected diol i.e. tert-butyl [(4S,6R)-6-((E)-2-{4-( 4-fluorophenyl)-6-isopropyl-2-
2

[methyl (methylsulfonyl)araino]-5-pyrimidinyl}ethenyl)-2,2-dimethyl-l,3-dioxan-4-
yl]acetate (I) with IN hydrochloric acid in diluted aqueous methanol. The hydrolyzed
mass is then subjected to the treatment of dilüte aqueous solution of sodium hydroxide and
pH of the solution is adjusted to 7.0 to 7.5 after complete conversion to its corresponding
sodium salt. The solution thus obtained is charcoalized and filtered over hyflosupercell
bed as well as through 5μ filter-pads providing the clear solution. The clear solution is
then reduced to 85% of volume by distilling-off the filtrate under reduced pressure below
50°C and the solution of reduced volume is again filtered through 5μ filter-pads. The clear
solution thus obtained is treated with a dilute aqueous solution of calcium chloride to
precipitate Rosuvastatin calcium as a white solid. Wet cake of Rosuvastatin calcium thus
obtained is then filtered and dried under vacuüm at 45°C to 50°C to afford dry amorphous
Rosuvastatin calcium (III).
This process is a one-pot synthesis (Scheme-1) wherein the sodium salt of Rosuvastatin
(II) is not isolated. The X-ray powder difïractogram confirms the amorphous property of
Rosuvastatin calcium.
3
Scheme-1

Description of the drawings accompanying the provisional speciflcation:
Fig 1. shows X-ray powder diffractogram of Rosuvastatin calcium obtained in accordance
with the present invention. It has an amorphous form, which is confirmed by its X-ray
powder diffractogram (Figure-1).
The present invention will be more fully understood from the example given below, but do
not exemplify the fbll scope of the invention.
Example: l
Hydrolysis ofprotected diol (I)
8.0 kg (13.85 mole) of tert-butyl [(4S,6R)-6-((E)-2-{4-(4-fluorophenyl)-6-isopropyl-2-
[methyl (methylsulfonyl) amino]-5-pyrimidinyl} ethenyl)-2,2-dimethyl-l,3-dioxan-4-yl]
acetate (I) is added into 200 L of methanol under stirring at 25°C to 35°C and reaction
mass is cooled to 5°C to 10°C.
19.2 L (19.18 mole) of 1.0 N HC1 is added into the reaction mass under stirring within 30
minutes by maintaining 5°C to 10°C temperature. The temperature of the reaction is raised
to 30°C to 35°C and it is maintained under stirring for 30 minutes. The reaction is analyzed
on thin layer chromatography and when hydrolysis is completed, the reaction mass is
allowed to cool 5°C to 10°C.
Example: 2
Sodium saltformation to obtain compound (IT)
Into the above-hydrolyzed mass, 26.4 L of 10% sodium hydroxide solution (66.0 mole) is
added under stirring within 30 minutes at 5°C to 10°C, 24.0 L of process water is also
added in the reaction mass within 30 minutes by maintaining 5°C to 10°C, the resulting
solution is stirred for 15 more minutes by maintaining the same temperature. Slowly
temperature of the reaction mass is raised to 20°C to 25°C and stirred for 30 minutes. The
reaction solution is analyzed on thin layer chromatography and when the sodium salt
formation is completed; pH of reaction mass is adjusted to 7.0 - 7.5 by adding IN HC1.
The dear solution thus obtained is treated with 0.4 kg of activated charcoal followed by
filtration through hyflosupercell bed and 5μ filter-pads with washing of 4.0 L of methanol.
4

Example: 3
Rosuvastatin calcium dry amorphous form (III)
The above filtrate is concentrated to it's 50% of volume by distillation under reduced
pressure, below 50°C temperature till it affords approximately 125 L of the reaction
solution. Two 80 L toluene washings were provided to the solution and again the reaction
solution is reduced to 50%, by distillation under vacuüm, below 50°C, Concentrated
solution thus obtained is allowed to cool at 20°C to 30°C. The entire volume of
concentrated solution is filtered through 5μ filter-pads followed by two 4.0 L washings of
process water. The filtered solution is cooled to 5°C to 10°C and a freshly prepared
aqueous calcium chloride solution (1.92 kg Calcium chloride (17.3 mole) in 8.0 L of
process water) is added into it within 30 minutes maintaining the same temperature.
Temperature of the reaction mass is then raised to 20°C to 30°C to afford the solid product.
Product thus obtained is centrifuged, spin dried and wet cake is finally dried under vacuüm
at 45°C to 50°C to afford 6.5 kg of dry calcium sak of (3S,5R,6E)-7-{4-(4-fIuorophenyl)-
6-isopropyl-2-[methyl(methyl sulfonyl) amino]-5-pyrimidinyl}-3,5-dihydroxy-6-
heptenoate i. e. Rosuvastatin Calcium.
The amorphous form of Rosuvastatin Calcium obtained is having purity 99.40 % (HPLC)
and water content 2.75% (w/w).
Rosuvastatin calcium thus obtained is having amorphous form, which is confirmed by its
X-ray powder diffractogram (Figure-1).
5

We claim:
1. One pot process of manufacturing of amorphous Rosuvastatin Calcium comprising the
steps of
(a) hydrolysis of the protected diol, (tertiary-butyl [(4S,6R)-6-((E)-2-{4-(4-
fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-
pyrimidinyl}ethenyl)-2)2-dimethyl-l)3-dioxan-4-yl]acetate) with 1.0 N
hydrochloric acid in aqueous methanol.
(b) conversion of the diol ((E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-
[methyl(methylsulfonyl) amino]pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-
enoic acid) to corresppnding sodium salt with suitable base in suitable solvent
combination.
(c) treatment of the solution of sodium salt with Calcium chloride solution to obtain
the amorphous form of Rosuvastatin Calcium salt ((E)-7-[4-(4-fluorophenyl)-6-
isopropyl-2-[methyl(methylsulfonyl) amïno] pyrimidin-5-yl] (3R,5S)-3,5-
dihydroxyhept-6-enoic acid calcium salt).

2. The process as.claimed claim l wherein in step (a) mmeral acid is used for the
hydrolysis of protected diol.
3. The process as claimed claim l wherein in step (a) the mineral acid used for
hydrolysis, is preferably dilute hydrochloric acid of 1.0 N concentration.
4. The process as claimed claim l wherein in step (a) the mole ratio of protected diol to
Hydrochloric acid used is 1: 1.5, most preferably 1:1.38.
5. The as claimed in claim l wherein in step (a) the temperature maintained during
hydrolysis process of Rosuvastatin protected diol is in the range 0-35°C.
6. The process as claimed claim l wherein in step (a) the temperature maintained during
addition of 1.0 N Hydrochloric acid is preferably 5°C to 10°C.
7. The process as claimed claim l wherein in step (a) the pH is adjusted to 7.0 - 7.5 by
adding l .0 N Hydrochloric acid, after the formation sodium salt.
6

7
8. The process as claimed claim l wherein the solvent used is aqueous alcohol of C-1 to
C-4, more preferably methanol.
9. The process as claimed claim l wherein in step (c) said sodium salt filtrate is
concentrated to its 50 % volume under reduced pressure.
10. The process as claimed claim l wherein in step (c) the concentrated solution is cooled
to IO°C to 30°C preferably 20°C to 30°C.
11. The process as claimed claim l wherein in step (c) the mole ratio of Rosuvastatin
protected diol to calcium chloride is 1:1.25.
12. The process as claimed claim l wherein in step (c) solution is further cooled to 0°C to
10°C preferably to 5°C to 10°C to precipitate Calcium salt of Rosuvastatin.

Documents:

459-mum-2004-abstract(15-4-2005).doc

459-mum-2004-abstract(15-4-2005).pdf

459-mum-2004-abstract(provisional)-(15-4-2004).doc

459-mum-2004-abstract(provisional)-(15-4-2004).pdf

459-MUM-2004-ANNEXURE 1-3(24-2-2014).pdf

459-MUM-2004-ANNEXURE 1-3(7-4-2014).pdf

459-mum-2004-claims(15-4-2005).doc

459-mum-2004-claims(15-4-2005).pdf

459-MUM-2004-CLAIMS(AMENDED)-(14-12-2012).pdf

459-mum-2004-correspondence 1(29-6-2008).pdf

459-mum-2004-correspondence 2(29-4-2009).pdf

459-MUM-2004-CORRESPONDENCE(13-12-2012).pdf

459-MUM-2004-CORRESPONDENCE(13-5-2013).pdf

459-MUM-2004-CORRESPONDENCE(16-9-2013).pdf

459-MUM-2004-CORRESPONDENCE(21-12-2012).pdf

459-MUM-2004-CORRESPONDENCE(21-6-2010).pdf

459-MUM-2004-CORRESPONDENCE(22-2-2013).pdf

459-MUM-2004-CORRESPONDENCE(26-7-2013).pdf

459-MUM-2004-CORRESPONDENCE(6-2-2014).pdf

459-MUM-2004-CORRESPONDENCE(9-2-2011).pdf

459-mum-2004-correspondence(ipo)-(25-5-2009).pdf

459-mum-2004-description(complete)-(15-4-2005).pdf

459-mum-2004-description(provisional)-(15-4-2004).pdf

459-mum-2004-drawing(15-4-2005).pdf

459-mum-2004-form 1(15-4-2004).pdf

459-mum-2004-form 18(29-1-2008).pdf

459-mum-2004-form 2(15-4-2005).doc

459-mum-2004-form 2(15-4-2005).pdf

459-mum-2004-form 2(provisional)-(15-4-2004).doc

459-mum-2004-form 2(provisional)-(15-4-2004).pdf

459-mum-2004-form 2(title page)-(provisional)-(15-4-2004).pdf

459-mum-2004-form 3(15-4-2004).pdf

459-mum-2004-form 5(15-4-2005).pdf

459-MUM-2004-GENERAL POWER OF ATTORNEY(14-12-2012).pdf

459-mum-2004-general power of authority(15-4-2004).pdf

459-MUM-2004-MARKED COPY(14-12-2012).pdf

459-MUM-2004-REPLY TO EXAMINATION REPORT(14-12-2012).pdf

459-MUM-2004-REPLY TO HEARING(24-2-2014).pdf

459-MUM-2004-REPLY TO HEARING(7-4-2014).pdf

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Patent Number

260931

Indian Patent Application Number

459/MUM/2004

PG Journal Number

22/2014

Publication Date

30-May-2014

Grant Date

28-May-2014

Date of Filing

15-Apr-2004

Name of Patentee

CADILA HEALTHCARE LIMITED

Applicant Address

ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD-380 015, GUJARAT, INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	VAKIL MANISH H	CADILA HEALTHCARE LIMITED, ZYDUS TOWER, SATELLITE CROSS ROAD, AHMNEDABAD-380 015, GUJARAT, INDIA
2	PATEL DHIMANT J	CADILA HEALTHCARE LIMITED, ZYDUS TOWER, SATELLITE CROSS ROAD, AHNEDABAD-380 015, GUJARAT, INDIA
3	RUPAPARA MAHESH L	CADILA HEALTHCARE LIMITED, ZYDUS TOWER, SATELLITE CROSS ROAD, AHNEDABAD-380 015, GUJARAT, INDIA
4	BHIMANI GIRISH H	CADILA HEALTHCARE LIMITED, ZYDUS TOWER, SATELLITE CROSS ROAD, AHNEDABAD-380 015, GUJARAT, INDIA
5	SUTARIYA PRAKASH M	CADILA HEALTHCARE LIMITED, ZYDUS TOWER, SATELLITE CROSS ROAD, AHNEDABAD-380 015, GUJARAT, INDIA
6	AGARWAL VIRENDRA KUMAR	CADILA HEALTHCARE LIMITED, ZYDUS TOWER, SATELLITE CROSS ROAD, AHNEDABAD-380 015, GUJARAT, INDIA

PCT International Classification Number

C07D239/42

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA