REFERENCE:
This application is a Patent of Addition filed under section 54 and rule 13(3) to main patent
application no.: 1556/DEL/2011 filed on June 01, 2011, the contents of which are being
incorporated herein by reference. The invention comprises an improvement in and a modification
of the invention claimed in the specification of the main patent applied for.
FIELD OF INVENTION:
The present invention relates to new polymorphic of crystalline Rosuvastatin calcium,
furthermore the present invention also reports novel processes for crystalline as well as
amorphous form of Rosuvastatin calcium which are used to treat a disease condition wherein
inhibition of HMG COA reductase is beneficial.
BACKGROUD OF INVENTION:
Rosuvastatin calcium is known by its chemical name as 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 of formula I as given below.
F
iPr
N N
NMe
MeO2S
COO-
OH OH
Ca++
2
FORMULA I
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.
EP-A1-0521471 describes in the preparation of Rosuvastatin calcium in powder form.
Rosuvastatin sodium is dissolved in water at room temperature and an aqueous calcium
3
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-fluorophenyl)-6-isopropy1-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl]-
(3R,5S)-3,5-dihydroxy-(E)-6-heptanoate with calcium hydroxide in a water / ethanol
solution.
WO 00/42024 discloses a crystalline form, hereafter referred to as Form A of -[4-(4-
flurophenyl)-6-isopropyl-2-(N-methyl-N-methyl sulfonyl amino)-pyrimidin-5-yl]- (3R,5S) -
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 discloses another crystalline form, hereafter referred to as Form B of 7-[4-
(4-flurophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R,5S)-
dihydroxy-hept-6-enoic acid Calcium salt which is prepared by slurrying of Amorphous
Rosuvastatin calcium in water at 40 ºC to get crystalline Form B. US20080194604 describes another
new process for the preparation.
US 20080194604 discloses another crystalline form, hereafter referred to as Form C of 7-[4-(4-
flurophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R,5S)-dihydroxyhept-
6-enoic acid calcium salt.
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 possibilities to modulate and
design improved drug products. As crystalline forms A, B, C etc of Rosuvastatin calcium
involves very tedious processes which are difficult to use at plant level since the material
becomes sticky when stirred initially, results dull colour of material and the product does not
4
crystallize after adding anti-solvent if dissolved in the solvent used. Some of these forms have
very 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-Nmethylsulfonylamino)-
pyrimidin-5-yl]-(3R,5S)-dihydroxy-hept-6-enoic acid calcium salt or
Rosuvastatin Calcium of improved colour having low water content & simplified process which is
easy to handle at plant level, to have a sufficient diversity on crystalline materials to optimize
manufacture, formulation and biological efficiency.
SUMMARY OF INVENTION:
This invention provides novel highly pure and stable crystalline forms hereinafter referred to as
form M and Form M2 of -[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 and
process for its manufacturing. Furthermore the invention also reports the novel processes for the
preparation of stable crystalline as well as amorphous Rosuvastatin calcium as confirmed by
their XRD as well as stability data.
DETAILED DESCRIPTION OF THE INVENTION:
The main aspect of the present invention is to provide a new crystalline polymorphic 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 (Rosuvastatin Calcium) of high purity which exhibits a
characteristic X-Ray diffraction pattern with characteristic peaks expressed in 2Ө values &
relative intensity as given below in tabular form), hereinafter designated as form M. XRD
diffractogram of Rosuvastatin calcium form M is attached as figure I.
2- Theta Relative intensity (%) (only
greater then 40 % mentioned)
6.83 63
8.14 49
9.15 73
10.23 43
11.30 95
15.60 42
17.82 48
19.17 100
19.44 68
5
20.30 80
20.82 80
22.01 65
22.85 74
24.14 56
24.56 40
According to another aspect of the present invention, a process for highly pure novel crystalline
form M of Rosuvastatin Calcium of formula I which comprises:
a) Hydrolysis of Rosuvastatin tert butyl or methyl ester of formula II in presence of aq.
Caustic solution in methanol.
OH
OH
O
O
N i-Pr
N
F
N
H3C
SO 2CH 3
R
R=Methyl or tert-butyl
Chemical Name: tert-Buty or methyl-(6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-
[methyl(methylsulfonyl) amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoate
Formula II
b) Washing of reaction mass with methyl tert butyl ether.
c) treatment of aq. layer with hydrochloric acid followed by addition of calcium chloride to
the reaction mass.
d) isolation of Rosuvastatin calcium by filtration & optionally drying.
e) dissolution of Rosuvastatin calcium (dry or wet) material in an aliphatic ketone.
f) crystallization of material by adding water.
g) filtration of resulting solid followed by drying to get new polymorphic form of
Crystalline Rosuvastatin calcium designated as form M.
According to another aspect, the ketone used is selected from acetone, ethyl methyl ketone,
diethyl ketone, dipropyl ketone, dibutyl ketone or a mixture thereof & water.
According to one more aspect of current invention, The ratio of aliphatic Ketone used in step e)
& Water used in step f) can be 10:5, 5:5 or even 3:8.
6
According to another aspect of the present invention, a process for highly pure novel crystalline
form M of Rosuvastatin Calcium of formula I which comprises:
a) Deprotection of Rosuvastatin diprotected tert butyl ester of formula III in acetonitrile
using dil Hydrochloric acid at room temperature.
O
O
CH3
CH3
O
O CH3
H3C CH3
N i-Pr
N
F
N
H3C
SO 2CH 3
Chemical Name: tert-butyl-2-((4R,6S)-6-((E)-2-(4(-(4-fluorophenyl)-6-isopropyl-2-(N-methyl
methylsulphonamido)pyrimidin-5-yl) vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate
Formula III
b) Confirmation of reaction completion after 2-4 hours via TLC/HPLC.
c) Hydrolysis of reaction mass in presence of aq. Caustic solution.
d) Again confirmation of reaction completion after 4-5 hours via TLC/HPLC.
e) Complete recovery of solvent using vacuum
f) Addition of water & methyl tert butyl ether and stirring for 10-15 min.
g) Layer separation
h) Slow addition of calcium chloride solution to reaction mass
i) Stirring for 4-6 hours
j) Isolation of product via filtration & drying at 50-60 °C.
k) Dissolution of Rosuvastatin calcium (dry or wet) of step j) in an aliphatic ketone.
l) Crystallization of material by adding water.
m) filtration of resulting solid followed by drying to get new polymorphic form of
Crystalline Rosuvastatin calcium designated as form M.
According to another aspect, the ketone used is selected from acetone, ethyl methyl ketone,
diethyl ketone, dipropyl ketone, dibutyl ketone or a mixture thereof.
7
According to one more aspect of current invention, the ratio of aliphatic Ketone used in step e) &
Water used in step f) can be 10:5, 5:5 or even 3:8.
According to one more aspect of current invention, the form M is is stable at 30°C with 65%RH
for 48 months & 40°C with 75%RH for 6 months for all ICH/EP/USP grade. The stability data is
as shown in the table below.
Storage
conditio
n
Storage
Period
(Month
s)
Descripti
on
Assay
(OAB)
Related Substances (HPLC) Wate
r
Ant
i-
Iso
mer
Lacto
ne
Meth
yl
Ester
Tert
Butyl
Ester
Dipro
tected
RT-
08
RT-
07
Indivi
dual
Unkn
own
Imp.
Total
Imp.
Limits A White
to
creamish
solid
98.0–
102.0%
w/w
NM
T
0.15
%
NMT
0.15
%
NMT
0.15
%
NMT
0.15
%
NMT
0.15
%
NMT
0.15
%
NMT
0.15
%
NMT
0.1%
NMT
1.5%
NMT
8.0%
Initial A white
solid
100.08 ND 0.02 ND ND ND ND 0.05 0.02 0.13 5.06
40°C/
75%
RH
1 A white
solid
100.03 ND 0.04 ND ND ND ND 0.05 0.03 0.14 5.65
2 A white
solid
99.93 ND 0.04 ND ND ND ND 0.05 0.02 0.15 5.59
3 A white
solid
100.03 ND 0.04 ND ND ND ND 0.05 0.02 0.13 5.66
6 A white
solid
99.59 ND 0.04 ND ND ND ND 0.04 0.02 0.12 5.63
30°C/
65%
RH
3 A white
solid
99.58 ND 0.05 ND ND ND ND 0.05 0.02 0.16 5.30
6 A white
solid
99.54 ND 0.04 ND ND ND ND 0.05 0.04 0.14 5.43
9 A white
solid
99.33 ND 0.04 ND ND ND ND 0.05 0.02 0.14 5.44
12 A white
solid
99.55 0.04 0.05 ND ND ND ND 0.06 0.02 0.17 5.55
18 A white
solid
99.70 0.03 0.04 ND ND ND ND 0.05 0.02 0.16 5.57
24 A white
solid
99.81
0.04 0.04 ND ND ND ND 0.05 0.02 0.15 5.72
36 A white
solid
99.75 0.04 0.04 ND ND ND ND 0.05 0.02 0.16 5.74
48 A white
solid
99.66 0.05 0.04 ND ND ND ND 0.05 0.02 0.16 5.90
According to yet another important aspect of current invention, the anti-isomer content in
Rosuvastatin calcium is very low or even not detected in comparison to other processes reported
in prior art.
8
Rosuvastatin Calcium Anti-Isomer (Formula IV)
F
iPr
CH2OH
N N
N
MeO2S CH3
4-(4-fluorophenyl)-6-isopropyl-2-[ (N-methyl-N-methylsulfonyl)
amino ] pyrimidine-5-yl-methanol
Mol For: C16H20O3FN3S
For Wt : 353.41
(Intermediate A)
F
N
N
N
CH2Br
i-Pr
H3CO2S
CH3
.
HP(IV)Ph
Ph
Ph
N-[4-(4-fluorophenyl)-5-(bromo methyl)-6-(isopropyl pyrimidin-2-yl)-N-methyl
methane sulfonamide triphenylphosphonium salt
Mol For: C14H34BrFN3O2PS
For Wt : 678.59
(Intermediate B)
9
H3C O
O
CH2
O O O
CH3
H3C
CH3
H3C CH3
tert-Butyl(4R-cis)-6-[(acetyloxy)methyl]-2,
2-dimethyl-1,3-dioxane-4-acetate
CAS# 154026-95-6
Mol For.: C15H26O6
For. Wt.: 302.36
(Intermediate C)
OHC O
O O O
CH3
H3C
CH3
H3C CH3
(4R-cis)-6-Formaldehydel-2,2-dimethyl-1,3-dioxane-
4-acetic-acid,1,1-dimethylethyl ester
CAS# 124752-23-4
Mol For.: C13H22O5
For. Wt.: 258.31
(Intermediate D)
According to still another aspect of the present invention, a novel process for preparation of
stable amorphous Rosuvastatin Calcium which comprises:
a) dissolution of any crystalline form of Rosuvastatin calcium in a halogenated hydrocarbon
such as methylene dichloride, chloroform, carbon tetrachloride or mixture thereof.
b) partial recovery of halogenated hydrocarbon & addition of anti-oxidant like butylated
hydroxyanisole, butylated hydroxytoluene or propyl gallate etc.
c) lowering of temperature of organic layer to 10-20 ºC.
d) addition of an aliphatic ether as anti solvent for crystallization of material.
e) further stirring for complete crystallization of material at 10-20 ºC.
10
f) isolation of material by filtration followed by drying at 50-60 ºC for 30-40 hours to get
amorphous Rosuvastatin calcium as confirmed by XRD pattern in figure II.
According to yet another aspect of present invention the aliphatic ether used is selected from
Diisopropylether, methyl tert butyl ether, dimethyl ether, diethyl ether or mixture thereof.
According to still another aspect of the present invention, a novel process for preparation of
stable amorphous Rosuvastatin Calcium which comprises:
a) dissolution of any crystalline form of Rosuvastatin calcium in a aliphatic ketone.
b) partial recovery of the aliphatic ketone & addition of anti-oxidant like butylated
hydroxyanisole, butylated hydroxytoluene or propyl gallate etc.
c) lowering of temperature of organic layer to 10-20 ºC.
d) addition of an aliphatic ether as antisolvent for crystallization of material.
e) further stirring for complete crystallization of material at 10-20 ºC.
f) isolation of material by filtration followed by drying at 50-60 ºC for 30-40 hours to get
amorphous Rosuvastatin calcium as confirmed by XRD pattern in figure II
According to another aspect the aliphatic ketone used is selected from acetone, ethyl methyl
ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or mixture thereof and
aliphatic ether used is selected from Diisopropylether, methyl tert butyl ether, dimethyl ether,
diethyl ether or mixture thereof.
According to still another aspect of the present invention, a novel process for preparation of
amorphous Rosuvastatin Calcium which comprises:
a) stirring of crystalline form M of Rosuvastatin calcium in a water.
b) Addition of sodium hydroxide solution & heating the reaction mass to 35-40°C.
c) Stirring for 30-60 minutes.
d) Washing with aliphatic ether followed by layer separation.
e) pH of aqueous layer containing product is adjusted to 8.5-9.5 at 25-30 °C.
f) addition of calcium chloride solution in water.
g) Stirring to ensure complete crystallization,
h) Drying at 50-60 °C for 10-15 hours.
11
i) Slurry washing of dried material in aliphatic ether containing anti-oxidant/ stabilizer like
butylated hydroxyanisole or butylated hydroxytoluene etc.
j) Re-filtered material & dried wet cake at 50-60 °C to get stable amorphous Rosuvastatin
calcium as confirmed by XRD pattern in figure II
According to another aspect the aliphatic ether used in step d) & i) is selected from
Diisopropylether, methyl tert butyl ether, dimethyl ether, diethyl ether or mixture thereof.
One more embodiment of the present invention is to provide a new crystalline polymorphic form
of 7-[4-(4-flurophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-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 2θ values
& relative intensity as given below in tabular form), hereinafter designated as form M2.
XRD diffractogram of Rosuvastatin calcium form M2 is attached as figure III of two different
sample.
2- θ Relative intensity (%) (only greater then 40 %
mentioned)
31.6 100
45.4 44
According to yet another embodiment, A novel process for the preparation of stable Rosuvastatin
Calcium crystalline Form M2 for 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 is
disclosed, which comprises:
a) Stirring of new polymorphic form ‘M’ as disclosed in previous embodiment, in
water.
b) Heating the reaction mass to 35-40°C, followed by addition of aq. caustic
solution
c) Stirring of reaction mass for one hour
d) Addition of aliphatic ether selected from Diisopropyl ether, methyl tert butyl
ether, dimethyl ether, diethyl ether or mixture thereof,
e) Layer separation
f) Adjusted pH of aq. layer to 8.5-9.5 with dilute Hydrochloric acid
g) Addition of calcium chloride solution followed by stirring to ensure complete
crystallization.
12
h) Isolation of product as wet cake
i) Drying of wet cake for 10-15 hours at temperature < 60 °C.
j) Slurry washing of dried material of step i) with aliphatic ether selected from
Diisopropyl ether, methyl tert butyl ether, dimethyl ether, diethyl ether or mixture
thereof, containing anti-oxidant/ stabilizer like butylated hydroxyanisole,
butylated hydroxytoluene or propyl gallate etc.
k) Filtration & drying of material at 50-60 °C to get stable Crystalline Form M2 of
Rosuvastatin calcium.
According to still another embodiment of current invention, The form M2 is is stable at 30°C
with 65%RH for 24 months & 40°C with 75%RH for 6 months for all ICH/EP/USP grade. The
stability data is as shown in the table below.
Plant
Batch
Plant Batch 01
Plant Batch 02
HP
LC
Puri
ty
(%)
Anti
-
isom
er
(%)
Lact
one
(%)
Ket
o
Imp
.
(%)
Other
impurities
(at RRT)
Assa
y
(%)
MC
(%)
HPL
C
Purit
y
(%)
Anti
-
isom
er
(%)
Lacto
ne
(%)
Ket
o
Im
p
(%
)
Other
impurities
(at RRT)
Ass
ay
(%)
MC
(%)
Initial
Results
99.8
5
0.04 0.03 ND 0.02%(0.86),
0.06%(1.48)
100.
19
4.1
0
99.8
2
0.05 0.03 ND 0.02%(0.86),
0.06%(1.48)
0.02% (1.86)
100
.69
4.7
5
Analytic
al
results
of RT
(after
3M)
99.7
2 0.05 0.04 0.14 0.03%(0.29),
0.02%(0.86) -- -- 99.7
2 0.05 0.03 0.0
9
0.02%
(0.13),
0.02%
(0.86),
0.04%(1.53),
0.02% (2.01)
-- --
Analytic
al
results
of RT
(after
6M)
99.2
9 0.04 0.03 0.55
0.02%(0.43),
0.02%(0.86),
0.03% (1.52)
0.02%(1.74)
-- -- 99.5
9 0.05 0.04 0.2
2
0.02%
(0.43),
0.02%
(0.86),
0.04%
(1.52),
0.02% (1.97)
-- --
Analytic
al
results
of RT
(after
9M)
99.0
8 0.05 0.03 0.74
0.03%(0.43)
0.02%(0.86)
0.03%(1.53)
0.02%(1.78)
99.5
1
4.2
5
99.4
3 0.05 0.04 0.3
8
0.03%(0.43),
0.02%(0.86),
0.03%(1.53),
0.02%(2.01)
99.
66
4.8
5
Analytic
al
results
of RT
(after
12M)
99.0
0 0.06 0.03 0.79
0.04%(0.43)
0.02%(0.86)
0.03%(1.53)
0.02%(1.77),
0.02%(1.80)
99.6
5
4.3
5
99.3
9 0.07 0.04 0.4
0
0.03%(0.43),
0.02%(0.86),
0.03%(1.54),
0.02%(2.04)
99.
77
4.8
5
13
According to one more embodiment of current invention, A novel process for the preparation of
Amorphous Rosuvastatin calcium using Form M2 is disclosed, which comprises
a) Charging of 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
or Rosuvastatin calcium in 5-10 times water.
b) Stirring at 30-35 °C for 30-60 minutes.
c) Isolation of amorphous Rosuvastatin calcium by routine filtration & drying at 50-60 °C.
The above mentioned invention is supported by the following non limiting examples.
EXAMPLES:
Example 1:
Preparation of 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 of tert-Butyl-(6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)
amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoate) was dissolved 1.0 liter of methanol.
The resulting solution was stirred for 10-30 min followed by addition of 10% of caustic solution.
The reaction mass is stirred for 3-4 hours followed by reaction monitoring by HPLC / TLC . The
solvent was recovered under vaccum to give crude product. Water 1.0 L added to the resulting
crude and stirred reaction mass. Methyl tertiary butyl ether 400 ml is added & reaction mass is
stirred for 15-20 minutes. The layer is separated and aqueous layer is filtered through celite bed
followed by addition of 20% calcium chloride solution (100 ml). The resulting suspension is
stirred for 3-4 hours filtered & washed with water. The material is dried at 50-60 ºC to afford
90.0 g of Rosuvastatin Calcium.
Example 2:
Preparation 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 M
To 90 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 prepared in example 1 is dissolved in 900
14
ml acetone followed by its filration via hyflow bed. The resulting mass is taken a clean and dried
round bottom flask. Water 500 ml is added to the filtered mass. The resulting mass is stirred for
6-10 hours. The resulting suspension is filtered and dried at 50-60 ºC to afford 63.0 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 M. (Water content = 3.18% &
HPLC Purity = 99.79%).
Example 3:
Preparation 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 M
To 90 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 prepared in example 1 is dissolved in 450
ml acetone followed by its filration via hyflow bed. The resulting mass is taken a clean and dried
round bottom flask. Water 450 ml is added to the filtered mass. The resulting mass is stirred for
6-10 hours. The resulting suspension is filtered and dried at 50-60 ºC to afford 63.0 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 M. (Water content = 3.26% &
HPLC Purity = 99.85%;).
Example 4:
Preparation 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 M
To 90 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 prepared in example 1 is dissolved in 270
ml acetone followed by its filration via hyflow bed. The resulting mass is taken a clean and dried
round bottom flask. Water 630 ml is added to the filtered mass. The resulting mass is stirred for
6-10 hours. The resulting suspension is filtered and dried at 50-60 ºC to afford 63.0 g of 7-[4-(4-
flurophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R,5S)-
15
dihydroxy-hept-6-enoic acid Calcium salt Polymorphic form M. (Water content = 3.26% &
HPLC Purity = 99.85%).
Example 5:
Example no 1 & hence 2, 3 & 4 are repeated using 7-[4-(4-fluorophenyl)-6-isopropyl-2-(Nmethyl-
N-methyl sulfonyl amino) pyrimidine-5-yl]-(3R,5S)-dihydroxy-5-oxo(E)-6-heptenate as
starting raw material to get new polymorphic form M of 7-[4-(4-flurophenyl)-6-isopropyl-2-(Nmethyl-
N-methylsulfonylamino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy-hept-6-enoic acid Calcium
salt or Rosuvastatin calcium. (Water content = 4.42% & HPLC purity = 99.76%).
Example 6:
100 gm of 4-(4-fluorophenyl)-6-isopropyl-2-[ (N-methyl-N-methylsulfonyl)amino ] pyrimidine-
5-yl-methanol (Intermediate A) is dissolved in mixture of Toluene (800 ml) & Acetonitirle (400
ml) at 10-30 ºC. Then reaction mass is cooled to 15-20 °C followed by addition of Potassium
tribromide (14 ml). The reaction mass is then stirred at 15-20 °C for 30 minutes. The completion
of reaction is confirmed via TLC/HPLC. After completion of reaction, reaction mass is quenched
in water & the crude product is recovered by recovery of solvent under vacuum. This crude
material is taken in toluene (100 ml) followed by stirring to get clear solution. Then this reaction
mass is heated to 80-90 °C followed by slow addition of Triphenylphosphine (72 g) in toluene.
The reaction mass is refluxed for 10-12 hours at 105-110 °C till reaction completion. After
reaction completion the reaction mass is cooled to RT followed by stirring for 1 hour &
filtration, so as to obtained product as wet cake. This wet cake is dried at 65-70 °C under vacuum
to get N-[4-(4-fluorophenyl)-5-(bromomethyl)-6-(isopropyl pyrimidin-2-yl)-N-methyl methane
sulfonamide triphenylphosphoniumsalt (Intermediate B) having HPLC purity = 99.85%.
Example 7:
100 gm of tert-Butyl(4R-cis)-6-[(acetyloxy)methyl]-2,2-dimethyl-1,3-dioxane-4-acetate
(Intermediate C) is dissolved in methanol (400 ml) & cooled the reaction mass to 0-5 °C under
stirring. Then potassium carbonate is added to reaction mass followed by stirring at 0-5 °C. The
reaction mass is then stirred at 0-5 °C for three hours till reaction completion. Complete recovery
of solvent is done under vacuum to get crude product, which is then taken in methylene chloride
16
(350 ml) and water washed organic layer followed by layer separation. The organic layer is
recovered under vacuum to get (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane- 4-aceticacid,
1,1-dimethylethyl ester (RTS05). This intermediate is then taken again in methylene
chloride (500 ml) followed by charging of 2,2,6,6,-tetramethylpiperidinooxy (1 g) & Potassium
bromide (10 g). To this reaction mass we add up mixture of 10% sodium bicarbonate (16.25 g)
solution & Sodium hypochlorite (280 ml; 10-12%) at -10 to -15 °C. The reaction is continued at
this temperature for 2 hours so as to complete reaction. After reaction completion reaction mass
is quenched in sodium Thiosulphate (25 g) solution in water, followed by stirring & layer
separation. The aqueous layer containing product is then extracted with methylene chloride (100
ml) . After that methylene chloride layer is recovered under vacuum to give 68 g (4R-cis)-6-
Formaldehydel-2,2-dimethyl-1,3-dioxane- 4-acetic-acid,1,1-dimethylethyl ester (Intermediate D)
as desired product having HPLC purity = 86.33%.
Example 8:
100 gm of N-[4-(4-fluorophenyl)-5-(bromomethyl)-6-(isopropyl pyrimidin-2-yl)-N-methyl
methanesulfonamidetriphenylphosphoniumsalt (Intermediate B) is taken in dimethylsulphoxide
(400 ml) under stirring and potassium carbonate (76 g) is added to it followed by addition of 50 g
(4R-cis)-6-Formaldehydel-2,2-dimethyl-1,3-dioxane- 4-acetic-acid,1,1-dimethylethyl ester
(Intermediate D) at room temperature. The reaction mass is then heated to 70-80 ° & stirred for
7-8 hours. After reaction completion temperature is reduced to 50°C followed by addition of
toluene. The reaction mass is now stirred for 1 hour at 25-35°C, followed by layer separation.
The organic layer is washed twice with water (700ml). Then organic layer is recovered so as to
be left with ¼ of the original volume. Then addition of hexanes (600 ml) is done for
crystallization of product at 50-60 °C. The reaction mass is stirred at this temperature followed
by cooling to reaction mass to 0-5 °C for filtration. The wet cake is dried at 40-50 °C for 4-6
hours to give 80 g 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
(Compound of Formula III) having HPLC purity = 97.98%.
Example 9:
17
100 gm of tert-butyl-2-((4R,6S)-6-((E)-2-(4(-(4-fluorophenyl)-6-isopropyl-2-(N-methyl methyl
sulphonamido)pyrimidin-5-yl) vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (Compound of
Formula III) is dissolved in Acetonitrile (500 ml) followed by stirring for 10-30 min. This is
followed by addition of dilute hydrochloric acid. Then reaction mass is stirred for 2-4 hours till
reaction completion. After confirmation of reaction completion by TLC/HPLC, caustic solution
is added to reaction mass and further stirred reaction mass to 3-4 hours. Then after completion of
second reaction, solvent is completely removed under vacuum at slightly elevated temperature.
This is followed by addition of first water (1000 ml) & then methyl tertiary butyl ether (400 ml)
& stirred so as to provide washing to product. Then layer separation is done and aq. layer
containing product is filtered via celite bed. This is followed by dropwise addition of Calcium
chloride solution & stirring for 4-6 hours to ensure complete crystallization. Then material is
filtered & dissolved in Acetone (500 ml). Then water (500 ml) is added to reaction mass and
stirred reaction mass for 6-10 hours. The resulting suspension is filtered and dried at 50-60 ºC to
afford 59.0 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 M. (Water
content = 3.22% & HPLC Purity = 99.87%, Anti-isomer content (Compound of formula IV) -
Nil).
Example 10:
100 gm 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 M is dissolved in 2.0
Liter of Acetone at 10-30ºC or at slight heating to ensure complete dissolution. The solvent is
recovered at atmospheric pressure to be left with 500 ml followed by filtration through celite
bed. The filtered layer is taken in clean and dry round bottom flask, followed by addition of
Butylated hydroxyanisole (0.5 g) and material is crystallized by the addition of methyl tertiary
butyl ether. The material is filtered and dried under vaccum at 50-60 ºC to afford 84.0 grams of
amorphous Rosuvastatin calcium as a white to off-white solid. (Water content = 3.05% & HPLC
Purity = 99.89 %)
Example 11:
18
100 gm 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 M is dissolved in 2.0
Liter of methylene chloride at 10-30ºC or at slight heating to ensure complete dissolution. The
solvent is recovered at atmospheric pressure to be left with 500 ml followed by filtration through
celite bed. The filtered layer is taken in clean and dry round bottom flask, followed by addition
of Butylated hydroxyanisole (0.5 g) and material is crystallized by the addition of diisopropyl
ether. The material is filtered and dried under vaccum at 50-60 ºC to afford 85.1 grams of
amorphous Rosuvastatin calcium as a white to off-white solid. (Water content = 3.12% % &
HPLC Purity = 99.86 %)
Example 12:
100 gm 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 M is taken in Water
(600 ml), under stirring followed by the addition of sodium hydroxide solution. The reaction
mass is stirred at 35-40 °C for 30-60 min followed by slow addition of methyltertbutyl ether (400
ml). Now the reaction is further maintained at this temperature for 30-40 minutes. After stirring
reaction mass is settled followed by layer separation. The Aq. layer containing product is filtered
via hyflow bed & any traces of solvents present is removed under vacuum. Now the aqueous
layer is cooled to 25-30°C followed by the pH adjustment to 8.5-9.58. Now calcium chloride
solution is added dropwise under stirring to ensure proper crystallization. The resulting material
is filtered as wet cake followed by its water washing (500 ml). Now the material is dried at 50-
60°C for 10-15 hours. Now this dried material is slurry washed in methyltertbutyl ether (200 ml)
containing butylated hydroxy anisole (0.5 g) for 5-10 minutes. The desired product is now
isolated as wet cake by filtration. The wet cake is now dried at 50-60 °C to get desired 82.5 g
amorphous Rosuvastatin Calcium as an offwhite solid. (Water content = 2.91 % & HPLC Purity
= 99.92 %).
Example 13:
Preparation of crystalline form M2 of 7-[4-(4-flurophenyl)-6-isopropyl-2-(N-methyl-N-methyl
sulfonylamino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy-hept-6-enoic acid Calcium salt
19
Crystalline Form M of 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), 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. Material is isolated as
wet cake followed by its drying at temperature 50-60 °C for 10-15 hours. This is followed by
slurry washing of dried material in methyl tertiary butyl ether (200 ml) containing butylated
hydroxyanisole (0.5 g) for 10-20 minutes. Then final material is filtered & dried at 50-60 °C for
6-10 hours to give Rosuvastatin calcium Crystalline form M2. (Water content = 3.95% &
HPLC Purity = 99.72 %). XRD attached Fig III.
Example 14:
Preparation of amorphous 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 using crystalline form
M2.
Crystalline Form M of 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
(1000 ml) water & stirred at 30-35°C for 30-60 minutes. The material is then isolated by
filtration followed by its drying at 50-60 °C to give amorphous 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. (Water content = 3.12% & HPLC Purity = 99.83%).

We Claim:
1. A novel polymorphic crystalline form ‘M’ of the compound 7-[4-(4-flurophenyl)-6-
isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R,5S)-
dihydroxy-hept-6-enoic acid Calcium salt, designated as form ‘M’ of
Rosuvastatin calcium of formula I or hydrates thereof.
F
iPr
N N
NMe
MeO2S
COO-
OH OH
Ca++
2
Formula I
2. Polymorphic crystalline form M of Rosuvastatin Calcium having characteristic
peaks as given below
2- Theta Relative intensity (%)
(Peaks having > 40% Intensity are mentioned)
6.83 63
8.14 49
9.15 73
10.23 43
11.30 95
15.60 42
17.82 48
19.17 100
19.44 68
20.30 80
20.82 80
22.01 65
22.85 74
24.14 56
24.56 40
3. A novel process for the preparation of highly pure crystalline form ‘M’ of the
compound 7-[4-(4-flurophenyl)-6-isopropyl-2-(N-methyl-N-methyl sulfonyl
21
amino)-pyrimidin-5-yl]-(3R, 5S)-dihydroxy-hept-6-enoic acid Calcium salt or
hydrates thereof according to claim 1, which comprises
i. Hydrolysis of tert-Butyl or methyl-(6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-
[methyl(methyl sulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-
enoate or Rosuvastatin tert butyl / methyl ester in an aliphatic alcohol such as
methanol with aq. Caustic solution.
ii. Isolation of Rosuvastatin calcium by addition of calcium chloride
iii. Recrystallization of resulting Rosuvastatin Calcium (wet or dry) using an
aliphatic ketone such as acetone, ethyl methyl ketone, diethyl ketone, dipropyl
ketone, dibutyl ketone or mixture thereof & water.
iv. Isolation of novel Rosuvastatin calcium crystalline form M by routine filtration
& drying.
4. A novel process for the preparation of highly pure crystalline form ‘M’ 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 or
hydrates thereof according to claim 1, which comprises
i. Deprotection of tert-butyl-2-((4R,6S)-6-((E)-2-(4(-(4-fluorophenyl)-6-iso
propyl-2-(N-methylmethylsulphonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-
1,3-dioxan-4-yl)acetate in acetonitrile using dilute hydrochloric acid.
ii. Hydrolysis of resulting material with aq. Caustic solution.
iii. Complete removal of acetonitrile from reaction mass under vacuum.
iv. Addition of water & methyl tert-butyl ether.
v. Layer separation
vi. Isolation of Rosuvastatin calcium by addition of calcium chloride to aq. layer.
vii. Recrystallization of resulting Rosuvastatin Calcium (wet or dry) using an
aliphatic ketone such as acetone, ethyl methyl ketone, diethyl ketone, dipropyl
ketone, dibutyl ketone or a mixture thereof & water.
viii. Isolation of novel Rosuvastatin calcium crystalline form M by routine filtration
& drying.
22
5. A process of step iii) of claim 3 & step vii) of claim 4, wherein the ratio of
aliphatic Ketone & water can be selected from 10:5, 5:5 or even 3:8.
6. A process of claim 4, in which anti-isomer content is very low (<0.1% by
HPLC) or even ‘Not Detected’.
7. A novel process for the preparation of stable amorphous Rosuvastatin Calcium
for 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 which comprises
i. Dissolution of new polymorphic form ‘M’ of Rosuvastatin calcium in
halogenated hydrocarbon such as methylene dichloride, chloroform, carbon
tetrachloride or mixture therof or an aliphatic ketone such as acetone, ethyl
methyl ketone, diethyl ketone, dipropyl ketone, dibutyl ketone or a mixture
thereof & water.
ii. Recovery of solvent from reaction mass of step (i) to left approximately 5 times
the volume w.r.t. the starting material or Rosuvastatin calcium & addition of
ant-oxidant/ stabilizer like butylated hydroxyanisole, butylated hydroxytoluene
or propyl gallate etc.
iii. Crystallization of amorphous Rosuvastatin Calcium salt by addition of an
aliphatic ether used is selected from Diisopropylether, methyl tert butyl ether,
dimethyl ether, diethyl ether or mixture thereof.
iv. Isolation & drying of filtered material to get amorphous Rosuvastatin calcium.
8. A novel process for the preparation of stable amorphous Rosuvastatin Calcium
for 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 which comprises
i. Stirring of new polymorphic form ‘M’ of Rosuvastatin calcium in water
ii. Heating the reaction mass to 35-40°C by adding aq.caustic solution
iii. Stirring of reaction mass for 30-40 minutes.
23
iv. Addition of alphatic ether aliphatic selected from Diisopropyl ether, methyl tert
butyl ether, dimethyl ether, diethyl ether or mixture thereof,.
v. Layer separation
vi. Filtration of aq. layer containing product via hyflow bed.
vii. Adjusted pH of aq. layer to 8.5-9.5 with dilute Hydrochloric acid.
viii. Addition of calcium chloride solution
ix. Stirring to ensure complete crystallization
x. Isolation of product as wet cake by filtration
xi. Slurry washing of wet cake with water
xii. Drying of wet cake for 10-15 hours at 50-60 °C.
xiii. Slurry washing dried material of step xii) with aliphatic ether selected from
Diisopropyl ether, methyl tert butyl ether, dimethyl ether, diethyl ether or
mixture thereof, containing anti-oxidant/ stabilizer like butylated
hydroxyanisole, butylated hydroxytoluene or propyl gallate etc.
xiv. Filtration & re-drying of material at 50-60 °C to get stable amorphous
Rosuvastatin calcium.
9. Another novel polymorphic crystalline form of the compound 7-[4-(4-
flurophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-
yl]-(3R,5S)-dihydro xy-hept-6-enoic acid Calcium salt, designated as form
‘M2’ of Rosuvastatin calcium of formula I or hydrates thereof
F
iPr
N N
NMe
MeO2S
COO-
OH OH
Ca++
2
Formula I
10. Polymorphic crystalline form M2 of Rosuvastatin Calcium having
characteristic peaks as given below
24
2- Theta Relative intensity (%)
(Peaks having > 40% Intensity are mentioned)
31.6 100
45.4 44
11. A novel process for the preparation of stable Rosuvastatin Calcium crystalline
Form M2 for the compound 7-[4-(4-flurophenyl)-6-isopropyl-2-(N-methyl-Nmethyl
sulfonyl amino)pyrimi din-5-yl]-(3R,5S)-dihydroxy-hept-6-enoic acid
Calcium salt which comprises
a) Stirring of new polymorphic form ‘M’ of Rosuvastatin calcium in water
b) Heating the reaction mass to 35-40°C by adding aq caustic solution
c) Stirring of reaction mass for 30-40 minutes
d) Addition of aliphatic ether selected from Diisopropyl ether, methyl tert butyl
ether, dimethyl ether, diethyl ether or mixture thereof,
e) Layer separation
f) Filtration of aq. layer containing product via hyflow bed.
g) Adjusted pH of aq. layer to 8.5-9.5 with dilute hydrochloric acid.
h) Addition of calcium chloride solution
i) Stirring to ensure complete crystallization
j) Isolation of product as wet cake
k) Drying of wet cake for 10-15 hours at 50-60 °C.
l) Slurry washing of dried material of step xi) with aliphatic ether selected
from Diisopropyl ether, methyl tert butyl ether, dimethyl ether, diethyl ether
or mixture thereof, containing anti-oxidant/ stabilizer like butylated
hydroxyanisole, butylated hydroxytoluene or propyl gallate etc.
m) Filtation & drying of material at 50-60 °C to get stable Crystalline Form M2
of Rosuvastatin calcium.
12. A novel process for the preparation of Amorphous Rosuvastatin calcium using
Form M2 of claim 11, 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-
25
enoic acid Calcium salt or Rosuvastatin calcium in water (5-10 times).
b) Stirring at 30-35 °C for 30-60 minutes.
c) Isolation of amorphous Rosuvastatin calcium by routine filtration & drying at 50-
60 °C.
13. The stabilizers used in the preparation of crystalline form M2 or Amorphous
Rosuvastatin calcium to increase their stability are selected from butylated
hydroxyanisole, butylated hydroxytoluene, propyl gallate etc or a mixture
thereof.
14. Rosuvastatin calcium polymorphic Form M of claim 1-4 is stable for 4 years
and even more at long term stability condition of 30°C & 65% RH as well as at
accelerated/ stress condition of 40-45°C & 75% RH.
15. Rosuvastatin calcium polymorphic Form M2 of claim 9-11, is stable for >2
years at long term stability condition of 30°C & 65% RH as well as at
accelerated/ stress condition of 40-45°C & 75%