FIELD OF INVENTION
The present invention relates to new polymorphic form M2 of crystalline Rosuvastatin
calcium, furthermore the present invention also reports novel processes for preparation of
crystalline form M2 of Rosuvastatin calcium which is used to treat a disease condition
wherein inhibition ofHMG COA reductase is beneficial.
BACKGROUD OF INVENTION
Rosuvastatin calcium is known by its chemical name as 7-[4-(4-flurophenyl)-6-
isopropyi-2-(N-methyi-N-methyl sulfonyl amino)-pyrimidin-5-yl]- (3R,5S) -dihydroxyhept-
6-enoic acid Calcium salt of formula I as given below.
OH
~
I ~ iPr
NYN
,...NMe
Me02S
OH
FORMULA I
coo·
ca ..
which is known to inhibit the HMG-CoA reductase, and subsequently suppress the bio
synthesis of cholesterol. Rosuvastatin calCium is useful in the treatment of hyper
cholesterolemia, hyperlipoproteinemia, and atherosclerosis. Rosuvastatin calcium may
form hydrates with a varying content of water.
2
IPO DELHI 13-08-2015 16 a9
I---
EP-A 1-05214 71 describes in the preparation of Rosuvastatin calcium in powder
form. Rosuvastatin sodium is dissolved in water at room temperature and an aqueous
calcium chloride solution is added dropwise. The collected precipitate is an amorphous
powder. U.S.Pat. No 6,777,552 discloses the preparation of Rosuvastatin calcium
through hydrolysis of methyl 7 -[ 4-( 4-fluoropheny 1)-6-isopropy 1-2-
[ methy l(methy lsulfonyl)amino] pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxy-(E)-6-
heptanoate .with calcium hydroxide in a water I ethanol solution.
WO 00/42024 discloses a crystalline form, hereafter referred to as Form A of -[4-(4-
fluropheny 1)-6-isopropyl-2-(N-methy 1-N-methy 1 sulfony I amino )-pyrimidin-5-y 1]- (3R,5 S)
-dihydroxy-hept-6-enoic acid calcium salt and hydrates thereof, which are prepared by
dissolving amorphous Rosuvastatin calcium form in a mixture of water and an organic
solvent such as acetone or acetonitrile under heating and then cooling the solution to
precipitate crystalline Form A.
WO 2005/023779 or US2010/222373 or US 7,932,387 discloses another crystalline
form, hereinafter referred to as Form B of 7-[ 4-( 4-flurophenyl)-6-isopropyi-2-(N-methyi-Nmethylsulfonylamino)-
pyrimidin-5-yl]-(3R,5S)-dihydroxy-hept-6-enoic acid Calcium salt
I
which is prepared by slurrying of Amorphous Rosuvastatin calcium in water at 40 °C to get
crystalline Form B.
WO 2005/023779 or US2010/222373 or US 8,436,167. disclosed yet another crystalline
form, hereinafter referred to as Form B-1, which is obtained by heating form B as
obtained above at temperature 60 °C at 0% RH.
3
IPD DELHI 13-08-281S
------------------------------------------------------------------------------------~---- -
US 20080194604 discloses another crystalline form, hereafter referred to as Form C of
7 -[ 4-( 4-fluropheny I )-6-isopropyl-2-(N-methyl-N -methy lsulfony I amino )-pyrimidin-5-yl](
3R,5S)-dihydroxy-hept-6-enoic acid calcium salt
US 7,994,178 of Tt:va disclosed & claimed another new polymorph of Rosuvastatin
calcium. It is prepared by stirring amorphous Rosuvastatin calcium in water at room
temperature for 24 hours followed by its cooling & stirring at 0-5°C to get new
polymorph.
PCT world patent application W02011/074016 of Matrix, claims two new polymorphic
forms R & S. Form R is prepared in Methyl-tert butyl ether & water while form S is
prepared from Rosuvasatin (8)-(-)-a-methylbenzyl amine salt, after its conversion to free
acid in ethyl acetate followed by treatment with caustic in Methyl-tert butyl ether,
followed by its treatment with calcium acetate.
Morepen's own Indian patent application 1556-DEL-2011, discloses polymorphic form
M, which· is prepared from Rosuvastatin calcium tert-butyl or methyl ester using
acetone-water.
Crystalline forms often show desired different physical and/or biological. characteristics
which may assist in the manufacturing or formulation of the active compound, to the
purity levels and uniformity required for regulatory approval. Crystalline forms of such
active compounds may also possess improved pharmacological characteristics, for
example, improved bioavailability, and therefore, novel crystalline forms offer enhanced
4
IPO DELHI 13-68-2.815 16:49
----- ----------
possibilities to modulate and design improved drug products. As crystalline forms A, B,
B-,1, C, M etc of Rosuvastatin calcium have high water content which can affect the
stability of the product, therefore there was a need for other crystalline forms of 7-[4-(4-
flurophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R,5S)dihydroxy-
hept-6-enoic acid calcium salt or Rosuvastatin Calcium having low water content,
to have a sufficient diversity on crystalline materials to optimize manufacture, formulation
and biological efficiency.
SUMMARY OF INVENTION:
This invention provides a novel highly pure crystalline form hereinafter referred to as form
M2 of [ 4-( 4-flurophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino )-pyrimidin-5-
yl]-(3R, 58)-dihydroxy-hept-6-enoic acid Calcium salt or Rosuvastatin calcium and process
for its manufacturing. Furthermore the invention also reports different novel processes for
the preparation of amorphous Rosuvastatin calcium as confirmed by XRD analysis.
DETAILED DESCRIPTION OF THE INVENTION:
First embodiment of the present invention is to provide a new crystalline polymorphic
form of 7 -[ 4-( 4-flurophenyl)-6-isopropyl-2-(N-methy 1-N -methylsulfony lamino )-pyrimidin-
5-yl]-(3R,5S) -dihydroxy-hept-6-enoic acid Calcium salt (Rosuvastatin Calcium) of high
purity which exhibits a characteristic X-Ray diffraction pattern with characteristic peaks
expressed in 29 values & relative intensity as given below in tabular form), hereinafter
designated as form M2.
5
I _, -
XRD diffractogram of Rosuvastatin calcium form M2 is attached as figure I & II of two
different samples.
2-0 Relative intensity(%) (only greater then 40%
mentioned)
31.6 100
45.4 44
According to second embodiment of the present invention, a process for novel crystalline
form M2 ofRosuvastatin Calcium of formula I which comprises:
1) Addition of tert-butyl-2-(( 4R,6S)-6-((E)-2-( 4( -( 4-fluorophenyl)-6-isopropyl-2-(Nmethyl
methylsulphonamido )pyrimidin-5-yl)vinyl)-2,2-dimethyl-1 ,3-dioxan-4-
yl)acetate of formula II as given below, in C1-C4 aliphatic alcohol.
H3C
CH3
F 0
CH3
0
0
N 0
CH3
H3C
CH3
N N i-Pr
S02CH3
Chemical Name: tert-butyl-2-(( 4R,6S)-6-((E)-2-( 4( -( 4-fluorophenyl)-6-isopropyl-2-(Nme
thy 1 me thy lsulphonamido )pyrimidin-5-yl)vinyl)-2,2-dimethy 1-1 ,3-dioxan-4-y l)acetate
{RTlO)
Formula II
6
.I :.P 'O. ·o.•· ·•E ·· L· ·H· 'T.JL.: 13.-88-2815 16
·• .r-
2) Stirring to dissolve
3) Slow addition of aq. hydrochloric acid
4) Heating the reaction mass & stirring till clarity of reaction mass
5) Stirring for 30-60 minutes & checking of reaction completion by TLCIHPLC.
6) Cooling of reaction mass to ambient temperature
7) Slow addition of caustic solution in 30-60 min, ensuring that temperature stnys
below 35 °C.
8) Stirring for 3-6 hours till reaction completion.
9) Recovery of solvent under vacuum to get semi solid mass.
10) Allowed the semi-solid mass to attain room temperature.
11) Addition of water & aliphatic ether for washing.
12) Stirring & layer separation.
13) Adjusting pH to 8.5-9.5 of aq. layer with hydrochloric acid.
14) Stirring & addition of calcium chloride solution
15) Stirring for complete crystallization ..
16) Filtration of solid
17) Washing of wet cake with water.
18) Drying wet cake at 45-60 °C in VTD/TD to get polymorphic form M2 of
Rosuvastatin calcium.
According to one aspect of the present invention, the C1-C4 aliphatic alcohol used in step 1
is selected from methanol, ethanol, !-propanol, 2-propanol, butanol, monoethylene glycol
& diethylene glycol or a mixture thereof.
7
~PO DELHI 13-08-2915 16 49
':-
According to another aspect of present invention the aliphatic ether used in step 11, is
selected from diisopropylether, methyl tert butyl ether, dimethyl ether, diethyl ether or
mixture thereof.
According to yet another aspect of present invention the temperature of stirring in step no 8
is 20-40 °C, more preferably 20-35 °C & most preferably 25-35 °C.
According to still another aspect of present invention the maximum temperature of solvent
recovery in step no 9 is 45-50 °C.
According to still another aspect of present invention the stirring time in step no 15) is 30
min to 8 hours, preferably 30 min to 5. hours, more preferably 30 min to 3 hours & most
preferably 30 min to 90 min.
According to third embodiment of the present invention, a process for novel crystalline
form M2 ofRosuvastatin Calcium of formula I which comprises:
a) Charging of any crystalline form of 4-(4-flurophenyl)-6-isopropyl-2-(N-methyl-Nmethyl
sulfonylamino)-pyrimidin-5"'yl-(3R,5S)-dihydroxy-hept-6-enoic
Calcium salt or crystalline Rosuvastatin calcium in water.
b) Stirring
c) slow addition of alkali metal or alkali earth metal base
d) Stirring & addition of aliphatic ether.
1e) Stirring & layer separation
acid
t) Heating aq. layer under vacuum to remove traces of ether maintain temperature
below40 °C.
8
IP.Q OELHI 1 3·- G8- 2·0 1 5 lG .4·9
,, _... ..
g) Cooling of reaction mass to room temperature
h) Addition of dilute hydrochloric acid to adjust pH to 8.5-9.5
i) Stirring & addition of calcium chloride solution
j) Stirring for complete crystallization.
k) Filtration of solid
I) Washing of wet cake with water.
m) Air drying of wet cake first at 25-30 °C for 1-2 hours followed by drying at 45-60
°C in VTD/TD to get polymorphic form M2 ofRosuvastatin calcium.
According to another aspect of present invention the aliphatic ether used in step d), is
selected from diisopropylether, methyl tert-butyl ether, dimethyl ether, diethyl ether or
mixture thereof.
According to yet another aspect of present invention the stirring time in step no d) is 60-90
minutes.
According to still another aspect of present invention the stirring time in step no j) is 30
min to 8 hours, preferably 30 min to 5 hours, more preferably 30 min to 3 hours & most
preferably 30 min to 90 min.
According to still one more aspect of present invention the alkali metal or alkali earth metal
base used in. step c) is selected from sodium hydroxide, potassium hydroxide or calcium
hydroxide.
9
l:P"-0· DELHfJE 13-08-201 !5 1.6 49
··---------
,, .. -
According to fourth embodiment of the present invention, a process for novel crystalline
form M2 ofRosuvastatin Calcium of formula I which comprises:
i. Charging of amorphous 4-( 4-fluropheny 1)-6-isopropyl-2-(N -methyl-Nmethylsulfonyl
amino)-pyrimidin-5-yl-(3R,5S)-dihydroxy-hept-6-enoic acid
Calcium salt or amorphous Rosuvastatin calcium in water.
ii. Stirring
iii. slow addition of alkali metal or alkali earth metal base
iv. Stirring & addition of aliphatic ether.
v. Stirring & layer separation
vi. Heating aq. Layer under vacuum to remove traces of ether
vii. Cooling of reaction mass to room temperature
viii. Addition of dilute hydrochloric acid to adjust pH to 8.5-9.5
ix. Stirring & addition of calcium chloride solution
x. Stirring for complete crystallization.
xi. Filtration of solid
xii. Washing of wet cake with water.
xiii. Air drying ofwet cake first at 25-30 °C for 1-2 hours followed by drying at 45-60
°C in VTD/TD to get polymorphic form M2 ofRosuvastatin calcium.
According to one aspect of present invention the aliphatic ether used in step iv), is selected
from diisopropylether, methyl tert-butyl ether, dimethyl ether, diethyl ether_ or mixture
ther,eof.
10
·I oo-
According to another aspect of present invention the stirring time in step no iv) is 60-90
minutes.
According to still another aspect of present invention the stirring time in step no x) is 30
min to 8 hours, preferably 30 min to 5 hours, more preferably 30 min to 3 hours & most
preferably 30 min to 90 min.
According to still one more aspect of present invention the alkali metal or alkali earth metal
base used in step iii) is selected from sodium hydroxide, potassium hydroxide or calcium
hydroxide ..
According to fifth embodiment of the present invention, a novel process for amorphous
Rosuvastatin Calcium using novel crystalline form M2 of Rosuvastatin Calcium which
comprises:
i. Charging of crystalline form M2 4-(4-flurophenyl)-6-isopropyl-2-(N-methyl-Nme
thy lsulfony 1 amino)-pyrimidin-5-yl-(3R,5S)-dihydroxy-hept-6-enoic acid
Calcium salt or Rosuvastatin calcium Form M2 in water.
ii. Heating of slurry at 30-35 °C.
iii. Stirring
iv. Isolation of product by filtration
v. Drying of wet cake as obtained m step iv) at 50-60 °C to get amorphous
Rosuvastatin Calcium.
According to one aspect of present invention the stirring time in step no iii) is 10 min to 60
minutes, preferably 20 minutes to 60 minutes & most preferably 30 minutes to 60 minutes.
11
IPD.DEhhl~ 13-GS-2015 lS:ag
,, ~-
The above mentioned invention is supported by the following non limiting examples.
EXAMPLES:
Example 1:.
Preparation of crystalline form M2 of 7-[4-(4-flurophenyl)-6-isopropyi-2-(N-methyl-
N-methyl sulfonylamino)-pyrimidin-5-yi]-(3R,5S)-dihydroxy-hept-6-enoic acid
Calcium salt
tert-butyl-2-(( 4R,6S)-6-((E)-2-( 4( -( 4-fluorophenyl)-6-isopropyl-2-(Nmethylmethylsulphonamido)
pyrimidin-5-yl)vinyl)-2,2-dimethyl-1 ,3-dioxan-4-yl)acetate
(1 00 g) was dissolved in methanol (1.5 Liter). The resulting solution was stirred for 10-15
min followed by addition of aq. hydrochloric acid. The reaction mass was heated to 35-40
oc & is stirred for 30-40 minutes followed by reaction monitoring by HPLC I TLC. The
rea9tion mass is then bought to room temperature followed by slow addition of caustic
solution in 30-60 minutes. The reaction mass is now stirred for 3-6 hours at 25-35 °C till
reaction completion on HPLC/TLC. After reaction completion confirmation, the reaction
mass is charcolized with activated carbon (5.0 g) at 25-35 °C. The reaction mass is then
fine filtered from hyflow or celite bed followed by washing of hyflow bed with methanol
(100 ml). The filtrated is then heated to 45-50 °C followed by its solvent recovery under
vacuum to get semi-solid product. Then methyl tert-butyl ether (400 ml) & water (1.0 Liter)
is charged to this semi-solid mass followed by stirring and layer separation. The organic
layer is discarded & the aq. layer containing product is fine filtered via hyflow or celite bed.
12
IPO DELH~ 13-08-2915 16:49
' . -
The aq layer is then heated & traces of methyl tertbutyl ether is removed under vacuum
from this layer. After removal oftraces, the pH ofaq. layer is adjusted to 8.5-9.5 using aq.
hydrochloric acid under stirring at 25-30 °C This is followed by addition of calcium
chloride solution (0.20 kg of calcium chloride in 1.0 Liter water). Now the reaction mass is
stirred for 30-90 minutes at 25-30 °C to ensure complete crystallization. Now the reaction
mass is filtered followed by slurry washing in water (300 ml). The material is then isolated
as wet cake by filtration followed by its drying at 45-60 °C for 10-15 hours. The semi dried
I
material is again given water washing so as to remove any undesired salts. After water
washing material is again filtered & finally dried in VTD/TD for 20-30 hours at 45-60 °C
till MC is not more than 5.0%, to give75 g of desired polymorph M2 of Rosuvastatin
calcium. (Water content= 3.80% & HPLC Purity= 99.79%). XRD attached as Fig I.
Example 2:
Preparation of crystalline form M2 of 7-[4-(4-flurophenyl)-6-isopropyi-2-(N-methyl-
N-methyl sulfonylamino)-pyrimidin-5-yi]-(3R,5S)-dihydroxy-hept-6-enoic acid
Cal,cium salt
Crystalline 7 -[ 4-( 4-flurophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino )-
pyrimidin-5-yl]-(3R,5S) -dihydroxy-hept-6-enoic acid Calcium salt (100 g) is added to
water (600 ml) followed by stirring. To this. caustic solution (15 g in 100 ml water) is
slowly charged. The resulting mass is then stirred for 60-90 minutes at 25-35 °C. After this
reaction mass is give washing with methyl tertbutyl ether (300 ml) followed. by its layer
separation. The aq. layer is kept aside while organic layer is extracted with water (100 ml),
13
IP 0 o:E:L HI 1 3 - 8 8 - 2 0 1 5 1 6. : 4 9
., . -
again followed by layer separation. Now both the aq. layers are combined and organic layer
is discarded. Now aq. layer is heated & traces of methyl tertbutyl ether is now removed
under vacuum followed by cooling of aq. layer to room temperature. Now adjust the pH of
aq. layer with dil. Hydrochloric acid (0.15 ml HCl in 100 ml of water) to 8.5-9.5. Now
calcium chloride solution (20 g in 100 ml water) is slowly added followed by stirring for
30-90 minutes at 25-30 °C. The resulting material is now filtered as wet cak~ fulluweu uy
slurry washing with water (500 ml). Now slurry is filtered again & dried at 25-30 first
followed by drying at 45-50 °C for 6-10 hours to afford 86 g of 7-[4-(4-flurophenyl)-6-
isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy-hept-
6-enoic acid Calcium salt Polymorphic form M2. (Water content= 3.88% & HPLC Purity
= 99.75 %). XRD attached as figure II.
Example 3:
Amorphous 7 -[ 4-( 4-flurophenyl)-6-isopropy 1-2-(N-methy 1-N-methy lsulfony lamino )pyrimidin-
5 -yl]-(3R,5S)-dihydroxy-hept-6-enoic acid Calcium salt (100 g) is added to
water (600 ml) followed by stirring. To this caustic solution (15 g in 100 ml water) is
sloWly charged. The resulting mass is then stirred for 60-90 minutes at 25-35 °C. After this
reaction mass is give washing with methyl tertbutyl ether (300 ml) followed by its layer
separation. The aq. layer is kept aside while organic layer is extracted with water (100 ml),
again followed by layer separation. Now both the aq. layers are combined and organic layer
is discarded. Now aq. layer is heated & traces of methyl tertbutyl ether is now removed
under vacuum followed by cooling of aq. layer to room temperature. Now adjust the pH of
aq. layer with dil. Hydrochloric acid (0.15 ml HCl in 100 ml of water) to 8.5-9.5. Now
14
I.P 0 D'E L. H l. 1 3 - 0 8 - 2 0 1 5 16 .Q· 9
' . -
calCium chloride solution (20 g in 100 ml water) is slowly added followed by stirring for
30-90 minutes at 25-30 °C. The resulting material is now filtered as wet cake followed by
slurry washing with water (500 ml). Now slurry is filtered again & dried at 25-30 first
followed by drying at 45-50 oc for 6-10 hours to afford 89 g of 7-[4-(4-flurophenyl)-6-
isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy-hept-
6-enoic acid Calcium salt Polymorphic form M2. (Water content = 3.95% & HPLC
Purity= 99.72 %): XRD attached Fig III.
Example3:
Crystalline form M2 of 7-[ 4-( 4-flurophenyl)-6-isopropyl-2-(N-methyl-Nmethylsulfonylamino
)-pyrimidin-5 -yl]-(3R,5S)-dihydroxy-hept-6-enoic acid Calcium salt
(100 g), as obtained in Example 1, 2 or 3 is added to water (800 ml) followed by stirring
at 30-35 °C for 30-60 minutes. After stirring the slurry is filtered and dried at 50-60 °C to
get amorphous Rosuvastatin calcium. (Water content= 3.12% & HPLC Purity= 99.83%).

We Claim:
1.
2.
3.
A novel polymorphic form of the compound 7-[4-(4-flurophenyl)-6-
isopropyl-2-(N-methyl-N-methyl sulfonyl amino)-pyrimidin-5-yl]- (3R,5S)
-dihydroxy-hept-6-enoic acid Calcium salt, designated as Form 'M2' of
Rosuvastatin Calcium of formula I or hydrates thereof.
~
· I ~ iPr
NYN
/NMe
Me02S
OH
coo·
ca••
Polymorphic form M2 of Rosuvastatin calcium having following two
characteristic peaks as given below:
29 Relative intensity (%)
31.6 100
45.4 44
A novel process for the preparation of crystalline form 'M2' of 7-[4-(4-
flurophenyl)-6-isopropyl-2-(N-methyl-N-methyl sulfonyl amino)-
pyrimidin-5-yl]- (3R,5S) -dihydroxy-hept-6-enoic acid Calcium salt or
hydrates thereof according to claim 1, which comprises
a) Deprotection of methyl or tert-butyl-2-((4R,6S)-6-((E)-2-(4(-(4-
fluorophenyl)-6-isopropyl-2-(N-methylmethylsulphonamido)pyrimidin-5-
16
IPO DELH~ 13-08-2015 16 49
' . -
4.
yl)vinyl)-2,2~dimethyl-1 ,3-dioxan-4-yl)acetate in an aliphatic alcohol with
aq. hydrochloric acid.
b) Hydrolysis of reaction mass of step a) by stirring for 3-6 hours in an Ct-C4
aliphatic alcohol with aq. caustic solution.
c) Solvent recovery under recovery to get semi-solid mass.
d) Washing of semi-solid mass with water & an aliphatic ether
e) Adjusting pH of aq. layer, as obtained from step d) after washing, to 8.5 to
9.5 with hydrochloric acid.
f) · Isolation ofRosuvastatin calcium by addition of calcium chloride
g) Stirring for 30-90 minutes to ensure complete crystallization
h) Isolation of novel Rosuvastatin calcium crystalline form M2 by routine
filtration & drying.
A process of claim 3, where the C1-C4 alcohol used in step a) & b) is
selected from methanol, ethanol, 1-propanol, 2-propanol, butanol,
monoethylene glycol & diethylene glycol or a mixture thereof.
5. . A process of claim 3, where the temperature in step b) is 25-35 °C & step c)
is 45-50 °C.
6. A novel process for the preparation of crystalline form 'M2' of the
compound 7 -[ 4-( 4-fluropheny l)-6-isopropyl-2-(N-methy 1-N-methy l sulfonyl
amino)-pyrimidin-5-yl]- (3R,5S) -dihydroxy-hept-6-enoic acid Calcium salt
or hydrates thereof according to Claim 1, which comprises
17
:I.P: 0 D·EL l'+I 1 3 - 0 8 - 2 0 1 5 1 6. 4 9
.. -
7.
8.
9.
a) Addition of any crystalline form of 7-[4-(4-flurophenyl)-6-isopropyl-2-(Nmethyl-
N-methyl sulfonyl amino)-pyrimidin-5-yl]- (3R,5S) -dihydroxyhept-
6-enoic acid Calcium salt in water
b) Stirring for 60-90 minutes & addition of an alkali metal I alkali earth metal
base
c) Washing with aliphatic ether
d) Adjusting pH of aq. layer, as obtained from step c) after washing, to 8.5 to
9.5 with hydrochloric acid.
e) Isolation of Rosuvastatin calcium by addition of calcium chloride
f) Stirring for 30-90 minutes to ensure complete crystallization
g) Isolation of novel Rosuvastatin calcium crystalline form M2 by routine
filtration & drying.
A process where the aliphatic ether used in step d) of claim 3 & step c) of
claim 6 is selected from diisopropylether, methyl tertbutyl ether,
dimethylether, diethylether or mixture thereof.
A process of where drying temperature ofRosuvastatin calcium form M2 in
step h) of claim 3 & step g) of claim 6 is 45-60 °C.
A process of claim 6-8, where Amorphous Rosuvastatin calcium is used as
starting material so as to convert it to Rosuvastatin calcium Form M2.
I 0. A process of claim 6, where alkali metal or alkali earth metal base used is
18
--~- --------
.. -
. •.
'.
selected from sodium hydroxide or potassium hydroxide.
11. · A novel process for the preparation. of Amorphous Rosuvastatin calcium
using Form M2 claimed in claim I, which comprises
a) Charging of crystalline form M2 of 7-[4-(4-flurophenyl)-6-isopropyl-2-(Nmethyl-
N-methylsulfonylamino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy-hept-
6-enoic acid Calc.ium salt or Rosuvastatin calcium in water.
b) Stirring at 30-35 °C
c) Isolation of amorphous Rosuvastatin calcium by routine filtration & drying
at 50-60 °C.
12. A process of claim 11, wherein stirring time in step b) is 10 to 60 minutes,
preferably 20 to 60 minutes & most preferably 30 to 60 minutes.
13. A process of claim 11, wherein the quantity of water used in step a) is 5 to
10 times w.r.t. the quantity ofForm M2 used.
14. Polymorphic form M2 of claim 1 ~ which is stable in ICH specifications for a ·
period of >2 years under storage condition of 2-8 ° or 8-15 °C in inert
atmosphere.