The present invention relates to a novel processes for preparation of highly pure Rosuvastatin
calcium (Formula I) almost free from antiisomer for control on one major antiisomer impurity
(Formula 11).
Formula I (Rosuvastatin calcium)
Chemical Name : (3R,5S,6E)-7-[4-(4-Fluorophenyl)-6-(1- methylethyl)-2-[methyl(methyl
sulfony1)mino]-5-pyrimidinyl]-3,5-dihydroxy-6-heptenoiacc id calcium salt.
CAS # 147098-20-2
F
Mat. Wt 480 53
Formula ZZ (Rosuvastatin Calcium antiisomer)
Chemical Name : (3R,5R,6E)-7-[4-(4-FIuorophenyl)-6-(-1m ethylethyl)-2-[methyl
(methylsulfonyl)mino]-5-pyrimidinyl]-3,5-dihydroxy-6-heptenoicacidcalciumsalt
CAS # 1094 100-06-7
BACKGROUD OF INVENTION:
Rosuvastatin Calcium (3R,5S,6E)-7-[4-(4-Fluorophenyl)-6-(l-methylethyl)-2-[methyl(methyl
sulfonyl)amino]-5-pyrimidinyl]-3,5-dihydroxy-6-heptenoic acid calcium sa1t.i~ a HMG-CoA
reductase inhibitor, a superstatin developed by Shionogi for the treatment of hyperlipidaemia
(Ann Rep, Shionogi, 1996, Dirt;jd Communication, Shionogi 8 Feb. 1999 and 25 Feb. 2000).
It can lower LDL-cholesterol and triglycerides more effectively than the first generation
drugs. Rosuvastatin calcium has the following structure being shown by 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.
US Patent No. RE 37314 (Reissue of US 5260440) discloses Rosuvastatin that is chemically
kr~dwra, s (3R,5S,6E)-7-[4-(4-Fluorophenyl)-6-(l-methylethyl)-2-[methyl(methylsulfonyl)
amino]-5-pyrimidinyl]-3,5-dihydroxy-6-heptenoaic~i d calcium salt., which are HMG CoA
reductase inhibitors and useful in the treatment of hypercholesterolemia, hyperlipoproteinemia
and atherosclerosis. In this patent, Rosuvastatin sodium is prepared from its methyl ester
according to Example 1 (6) by adding sodium hydroxide to a solution of the methyl ester in
ethanol, followed inter alia by distillation, followed by addition of ether to the residue
obtained from distillation. When preparing a salt of Rosuvastatin, the present applicants
found. that diethyl ether may not be used in production; after distillation of the solvent, the
n-r%-7%l
present applicants obtained a viscous oil that hardly precipitates in diet@:&th&, i+hk%ay in
results in formation of many diastereoisomeric impurities which possible.
EP-A1-0521471 describes in example 7 the preparation of Rosuvastatin calcium in
powder form. Rosuvastatin sodium is dissolved in water at room temperature and an aqueous
cdcium 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
hydrolysation of methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]
pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxy-(E)-6-heptanoatew ith calcium hydroxide in a water
/ ethanol solution. The compound is not isolated from the solution to characterize an
amorphous or crystalline state.
W02005068435 discloses a method of preparation of the amorphous hemi-calcium salt of
Rosuvastatin by a one-pot manufacturing process from the Rosuvastatin ester or lactone
intermediate. The invention describes use of alkali metal hydroxides for the purpose of the
hydrolysis of Rosuvastatin ester or lactone intermediate in a suitable solvent system, which
is subjected to the treatment of Calcium acetate or Calcium hydroxide to afford amorphous
hemi calcium salt of Rosuvastatin without isolating any intermediate alkali metal salt of
Rosuvastatin.
WO 2005/040134 A1 discloses the amorphous Rosuvastatin calcium having purity of more
than 99% with diastereoisomeric impurity less than 0.5% by HPLC. The process for
preparation of amorphous Rosuvastatin calcium, from a solution ofRosuvastatin
calcium in one or more organic solvents, recovering the amorphous form of Rosuvastatin
calcium by removal of solvent i.e. either by distillation, distillation under vacuum,
evaporation, spray drying, freeze-drying, lyophilization, filtration, filtration under
vacuum, decantation, and centrifugation is also in the scope of present invention.
WO 20051040134 discloses a process that is reported to reduce the diastereoisomer content of
Rosuvastatin through lactonization, or through conversion of amorphous rosuvastatin to
crystalline Rosuvastatin and subsequent conversion to the amorphous form.
US 6,844,437 B1 and US 6,784,171 B2 provides the process for the preparation of tert-butyl
(E)-(6- (2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)aino]pyimidin-5-yl]
vinyl)-(4R,6S)-2,2-dimethyl[I ,3]dioxan-4- y1)acetate which comprises reaction of diphenyl [4-
(4-flourophenyl)-6-isopropyl-2-[methyl)methylsulfonyl)aino[pyimid-in-5-lmethyl]phosphine
oxide with tert-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl]acetaitne the presence
of a strong base
Rosuvastatin is an enantiomerically pure compound having two chiral centers at positions 3 and
5 of the molecule. Two of the four diastereoisomers of Rosuvastatin calcium are (3R,5R) and
(3R,5S) derivatives. These diastereoisomers can be detected by reverse phase HPLC.
The synthetic process disclosed in various patents mentioned above including basic product
patent US RE37,314E for Rosuvastatin involves reduction of a keto-ester of a Rosuvastatin at
carbon 5 to obtain a dial ester. This reduction at position 5 is a standard typical step in the
synthesis of statins. This reduction step however can result in diastereoisomeric impurities.
The product mixture of a reaction rarely is a single compound pure enough to comply with
pharmaceutical standards. Side products and byproducts of the reaction and reagents used in
the reaction will, in most cases, be present. At certain stages during processing of the
rosuvastatin contained in the product mixture into an active pharmaceutical ingredient
("API"), the Rosuvastatin must be analyzed for purity, typically by HPLC or GC analysis, to
determine if it is suitable for continued processing or ultimately for use in a pharmaceutical
product. The Rosuvastatin does not need to be absolutely pure. Absolute purity is a theoretical
ideal that is unattainable. Rather, there is purity standards intended to ensure that an API is
not made less safe for clinical use because of the presence of impurities. In the United States,
the Food and Drug Administration guide- lines recommend that applicants limit some
impurities to below 0.1 %.
As there is no process of Rosuvastatin calcium reported in literature for control on antiisomer,
therefore there was a need to develop a process for preparation of Rosuvastatin
calcium almost free from antiisomer.
SUMMARY OF INVENTION:
This invention provides an improved process for the preparation of Rosuvastatin calcium
(Compound of formula I) almost free from antiisomer (Compound of formula 11). Various
examples have been provided herein which establish that in different experimental conditions,
antiisomer formation is different. Therefore our aim of this invention is to establish experimental
conditions which minimize the formation of antiisomer (compound of formula 11). So that yield
loss during repeated purification for removal of anti-isomer can be avoided & process can be
made commercially viable.
DETAILED DESCRIPTION OF THE INVENTION:
According to the first embodiment of the present invention, a process for preparation of highly
pure Rosuvastatin calcium of formula I which comprises:
1. Dissolving tert-butyl-2-((4R,6S)-6-((E)-2-(4(-(4-fluorophenyl)-6-isopropyl-2-~-methyl
methylsulphonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl- 1,3-dioxan-4-y1)acetate in
aliphatic straight chain or branched chain alcohol.
2. Slow addition of aq. hydrochloric acid.
3. Heating of reaction mass.
4. Stirring of reaction mass.
5. Checking of reaction completion by HPLC.
6. Cooling of reaction mass to 35-30 "C after reaction completion.
7. Addition of caustic solution.
8. Stirring of reaction mass for 8 - 10 hours.
i 1
9. Checking of reaction completion by HPLC.
10. Heating the reaction mass & complete recovery of solvent after reaction completion.
11. adding water to reaction mass & stirring
12. Adding methyl tertiary butyl ether to the reaction mass of step (1 1)
13. Layer separation.
14. Adjusting the pH of reaction mass to 8.5-9.5 with dilute hydrochloric acid.
15. Adding aq.calcium chloride solution.
16. Stirring till complete crystallization
1% Filtration of resulting solid
18. Drying of wet cake at 45-60 "C for 10-20 hours to get pure Rosuvastatin calcium.
According to one aspect of the present invention, the C1-C4 aliphatic alcohols used in step (1) are
selected from methanol, ethanol, I-propanol, 2-propanol, butanol, monoethylene glycol &
diethylene glycol or a mixture thereof.
According to second aspect of present invention, the strength of hydrochloric acid used in step
(2) above was 0.2 N.
According to third aspect of present invention, the temperature in step (3) & (4) is 35-40 OC.
According to fourth aspect of present invention the stirring time in step (4) is 3-4 hours.
According to fifth aspect of present invention, the temperature of stirring in step (8) is 25-35 OC
& time of stirring is 3-6 hours.
. I t
According to sixth aspect of present invention, the temperature of heating in step no (10) is 45-
According to second embodiment of the present invention a process similar as mentioned above
if the strength / quantity of hydrochloric acid used is increased, then the Rosuvastatin anti-isomer
formed is increased to about 1.08% on HPLC.
According to third embodiment of present invention a process as mentioned above if the solvent
used for reaction is an aliphatic nitrile such as acetonitrile or propionitrile or mixture thereof in
place of C1-C4 aliphatic alcohol. Then the anti-isomer impurity formation is increased to about
1.03% on HPLC.
According to fourth embodiment of current invention if solvent used for reaction is changed to
an aliphatic nitrile such as acetonitrile or propionitrile or mixture thereof & strength 1 quantity of
Hydrochloric acid being used are increased simultaneously, then the anti-isomer formation is
highly increased to 2.97% on HPLC.
According to yet another embodiment of current invention, a novel HPLC method of analysis of
Rosuvastatin calcium is disclosed herein which is capable of separating all major potential
impurities of Rosuvastatin Calcium (list given below).
Hence from above mentioned parameters, it can be shown that process as per the first
embodiment is the best for the preparation of Rosuvastatin calcium which gives the Rosuvastatin
calcium with minimum content of Anti-isomer impurity of formula 11.
LIST OF MAJOR 1 POTENTIAL IMPURITIES:
1. Rosuvastatin Anti-isomer =7-[4-(4-flurophenyl)-6-isopropyl-2-(N-methyl-N-methyl
sulfony1arnino)-pyrimidin -5-yl]-(3R,5R)-dihydroxy-6(E)-heptenoic acid calcium salt
APR 2011
2. Rosuvastatin Lactone = N-(4-(4-fluorophenyl)-5-((E)-2-((2S,4R)-4-hydroxy-6-
oxotetrahydro-2H-pyran-2-yl)vinyl)-6-isopropylpyrimidin-2-yl)-N-methyl
methanesulfonamide
3, Rosuvastatin methyl ester = (3R, 5S, 6E)-7-[4-(4-fluoropheny1)-6-isopropyl-2-(Nmethyl-
N-methyl sulfonyl amino) pyrimidine-5-yl]--dihydroxy-5-0~0-6-heptenate.
4. Rosuvastatin tert-Butyl ester =(3R,5S,6E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-
[(methanesulphonyl)methyl amino] pyrimidin-5-yl]-3,5-dihydroxy hept-6-enoic acid tert-
Butyl ester
5. Diprotected Rosuvastatin =Tert-Butyl-2-((3R,5S)-6-((E)-2-(4(-(4-fluorophenyl)-6-
isopropyl-2-(N-methyl methylsulphonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl- 1,3-
dioxan-4-y1)acetate
6. FIMP Aldehyde =4-(4-Fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)
aminolpyrimidinyl-5-yl-carbaldehyde
7. FIMP Alcohol =4-(4-fluoropheny1)-6-isopropyl-2-[( n-methyl-n-methylsulfonyl)amino]
pyrimidine-5-yl-methanol
Method for Related substances by HPLC
Reagents
Acetic Acid (HPLC Grade)
Acetonitrile (HPLC Grade)
Methanol (HPLC Grade)
Milli Q water
Preparation of 0.2% Acetic acid (vlv)
Dilute 2.0 mL acetic acid in 1000 ml water. Filter through 0.45 p filter paper.
Mobile phase Composition
Mobile phase A : 0.2% Acetic acid (vlv)
Mobile phase B : Methanol: Acetonitrile (5050)
Slight adjustment in mobile phase is allowed to achieve the retention time.
Preparation of Diluent
Mobile phase A: Mobile phase B (50: 50)
Chromatographic Parameters:
Use a suitable High Performance Liquid Chromatograph (HPLC) with following parameters
Column Durashell C18,250 x 4.6mrn, 5p Particle
size or equivalent
Flow rate 1.2 mllmin
Detector UV at h=248 nm
Injection volume : 20 pl
Column Temp. 40° C
Run time 50 min
Delay time 10 min
Gradient programme:
Preparation of Blank
Time
0
15
25
5C
5 1
Use diluent as blank
Preparation of System Suitability solution
Solution A: Weigh accurately about 5 mg each of Rosuvastatin Calcium, Rosuvastatin Lactone
Rosuvastatin Methyl Ester, Rosuvastatin t-Butyl Ester, FIMP Aldehyde and FIMP Alcohol in lOml
%A
5 0
5 0
20
20
50
volumetric flask. Dissolve it in diluent and make volume up to the mark with diluent (Store the
solution at 4OC for further use).
%B
5 0
5 0
80
80
5 0
Curv
--
6
6
6
1
Solution B: Weigh accurately about 5 mg of Diprotected Rosuvastatin in 10 ml volumetric flask
dissolve and make up with methanol. (Store the solution at 4OC for further use).
Accurately transfer 1 ml each of Solution: A and Solution: B in 100 ml volumetric flask and make up
to mark with diluent (store the solution at 4OC for further use).
Procedure
Inject 20 p1 each of blank (diluent) and system suitability solution if the system suitability passes
inject the sample preparation
Suitability requirement
Resolution NLT 1.5 between Rosuvastatin Lactone and FIMP Alcohol
Resolution NLT 1.5 between FIMP Alcohol and Rosuvastatin Methyl Ester
Preparation of Sample Solution.
Weigh accurately about 50mg sample in 100mi volumetric flask, dissolved it in diluent and make
volume up to the mark with diluent.
The retention time of Rosuvastatin Calcium is about 13.2 min approximately
Calculations for impurities
Impurity
Rosuvastatin Calcium
Rosuvastatin Anti-isomer
Rosuvastatin Lactone
FIMP Alcohol
Rosuvastatin Methyl Ester
FIMP Aldehyde
Rosuvastatin t-Butyl Ester
Diprotected Rosuvastatin
AT
% Impurity = ------ X 100
AS
Relative Retention time w.r.t. Rosuvastatin
1 .OO
1.08 approx
1.52 approx
1.57 approx
1.62 approx
1.96 approx
2.06 approx
2.87 approx
Where,
AT = Area of individual impurity in test.
AS = Sum of the area of allpeaksfiom the test
Note: Neglect the impurities which are less than 0.02%.
The above mentioned invention is supported by the following non limiting examples /
comparative examples.
EXAMPLES:
Example 1:
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)
is dissolved in methanol (1500 ml) followed by its stirring at 2530°C for 10-15 minutes to
ensure its complete dissolution. Hydrochloric acid solution 0.2 N (200 ml) was added slowly at
25-30 "C. The reaction mass is heated to 35-40 "C under stirring till reaction completion. The
reaction is monitored by TLC/HPLC. Then the reaction mass is cooled to 25-35 "C followed by
addition of 10% caustic solution (1 00 ml) under reaction mass and the reaction mass is stirred at
25-35 "C till reaction completion on HPLCITLC. The solvent is removed completely from
reaction mass under vacuum at temperature 45-50 "C and water (1000 ml) is added followed by
its stirling for 10-15 minutes at 25-30 "C. To this reaction mass, methyl tert butyl ether (400 ml)
is added followed by stirring and layer separation. Aqueous layer obtained after water washing
was filtered via hyflow bed & traces of methyl tertiary butyl ether are removed under vacuum
keeping the temperature below 45 "C. Then the reaction mass was cooled to 25-30 "C & pH is
adjusted to 8.5-9.5 with dilute hydrochloric acid followed by addition of calcium chloride
solution & stirring at 20-30 "C for 6-8 hours till complete crystallization. The resulting solid is
filtered and dried at 45-60 "C for 10-20 hours to get crystalline Rosuvastatin calcium.
Yield = 0.84; Purity by HPLC > 99 %; Antiisomer = 0.07 %.
2 APR 20U
Example 2:
tert-butyl-2-((4R,6S)-6-((E)-2-(4(-(4-fluorophenyl)-6-isopropyl-2-~-
methylmethylsulphonamido) pyrimidin-5-y1)vinyl)-2,2-dimethyl-1 ,3-dioxan-4-1)acetate (1 00 g)
is dissdved in acetonitrile (1500 ml) followed by its stirring at 25-30°C for 10-15 minutes to
ensure its complete dissolution. Hydrochloric acid solution 0.2 N (200 ml) was added slowly at
25-30 OC. The reaction mass is heated to 35-40 "C under stirring till reaction completion. The
reaction is monitored by TLCmPLC. Then the reaction mass is cooled to 25-35 "C followed by
addition of 10% caustic solution (100 ml) under reaction mass and the reaction mass is stirred at
25-35 "C till reaction completion on HPLCITLC. The solvent is removed completely from
reaction mass under vacuum at temperature 45-50 "C and water (1000 ml) is added followed by
its stirring for 10-15 minutes at 25-30 "C. To this reaction mass, methyl tert butyl ether (400 ml)
is added followed by stirring and layer separation. Aqueous layer obtained after water washing
was filtered via hyflow bed & traces of methyl tertiary butyl ether are removed under vacuum
keeping the temperature below 45 "C. Then the 'reaction mass was cooled to 25-30 OC & pH is
adjusted to 8.5-9.5 with dilute hydrochloric acid followed by addition of calcium chloride
solution & stirring at 20-30 "C for 6-8 hours till complete crystallization. The resulting solid is
filtered and dried at 45-60 "C for 10-20 hours to get crystalline Rosuvastatin calcium.
Yield = 0.80; Purity by HPLC = 98.09 %; Antiisomer = 1.08 %.
Example 3:
tert-butyl-2-((4R,6S)-6-((E)-2-(4(-(4-fluorophenyl)-6-isopropyl-2-~-
methylmethylsulphonarnido) pyrimidin-5-y1)vinyl)-2,2-dimethyl- 1,3-dioxan-4-y1)acetate (1 00 g)
is dissolved in methanol (1500 ml) followed by its stirring at 2530°C for 10-15 minutes to
ensure its complete dissolution. Hydrochloric acid solution 0.5 N (200 ml) was added slowly at
25-30 "C. The reaction mass is heated to 35-40 "C under stirring till reaction completion. The
reaction is monitored by TLCIHPLC. Then the reaction mass is cooled to 25-35 "C followed by
addition of 10% caustic solution (1 00 ml) under reaction mass and the reaction mass is stirred at
25-35 "C till reaction completion on HPLCITLC. The solvent is removed completely fiom
reaction mass under vacuum at temperature 45-50 "C and water (1000 ml) is added followed by
its stirring for 10-15 minutes at 25-30 "C. To this reaction mass, methyl tert butyl ether (400 ml)
is added followed by stirring and layer separation. Aqueous layer obtained after water washing
was filtered via hyflow bed & traces of methyl tertiary butyl ether are removed under vacuum
keeping the temperature below 45 "C. Then the reaction mass was cooled to 25-30 "C & pH is
adjusted to 8.5-9.5 with dilute hydrochloric acid followed by addition of calcium chloride
solution & stirring at 20-30 "C for 6-8 hours till complete crystallization. The resulting solid is
filtered and dried at 45-60 "C for 10-20 hours to get crystalline Rosuvastatin calcium.
Yield = 0.80; Purity by HPLC = 96.44 %; Antiisomer = 1.03 %.
Example 4:
tert-butyl-2-((4R,6S)-6-((E)-2-(4(-(4-fluorophenyl)-6-isopropyl-2-(Nmethylmethylsulphonamido)
pyrimidin-5-y1)vinyl)-2,2-dimethyl- 1,3-dioxan-4-y1)acetate (1 00 g)
is dissolved in acetonitrile (1500 ml) followed by its stirring at 2530°C for 10-15 minutes to
ensure its complete dissolution. Hydrochloric acid solution 0.5 N (200 ml) was added slowly at
25-30 "C. The reaction mass is heated to 35-40 "C under stirring till reaction completion. The
reaction is monitored by TLCIHPLC. Then the reaction mass is cooled to 25-35 "C followed by
. * I ' 1 addition of 10% caustic solution (1 00 ml) under reaction mass and the reaction mass is stirred at
25-35 "C till reaction completion on HPLCITLC. The solvent is removed completely from
reaction mass under vacuum at temperature 45-50 "C and water (1000 ml) is added followed by
its stirring for 10-15 minutes at 25-30 "C. To this reaction mass, methyl tert butyl ether (400 ml)
is added followed by stirring and layer separation. Aqueous layer obtained after water washing
was filtered via hyflow bed & traces of methyl tertiary butyl ether are removed under vacuum
keeping the temperature below 45 "C. Then the reaction mass was cooled to 25-30 "C & pH is
adjusted to 8.5-9.5 with dilute hydrochloric acid followed by addition of calcium chloride
solution & stirring at 20-30 "C for 6-8 hours till complete crystallization. The resulting solid is
filterea and dried at 45-60 "C for 10-20 hours to get crystalline Rosuvastatin calcium.
Yield = 0.86; Purity by HPLC = 95.68 %; Antiisomer = 2.97 %.

We claim:
1. An improved process for a preparation of highly pure Rosuvastatin calcium of formula I
which comprises
i. dissolving tert-butyl-2-((4R,6S)-6-((E)-2-(4(-(4-fluorophenyl)-6-isopropyl-2-~-methyl
methylsulphonamido)pyrimidin-5-yl)vinyl)-272-dimethyl-173-dioxan-4-yl)acetate in a
solvent.
ii. slow addition of aq. hydrochloric acid.
iii. heating & stirring of reaction mass.
iv. checking of reaction completion by HPLC.
v. cooling of reaction mass to 35-30 OC after reaction completion.
vi. addition of caustic solution.
vii. stirring of reaction mass for 8 - 10 hours.
viii. checking of reaction completion by HPLC.
ix. heating the reaction mass & complete recovery of solvent after reaction completion.
x. addition of water to reaction mass & stirring
xi. addition methyl tertiary butyl ether to the reaction mass of step (x)
xii. layer separation.
xiii. adjusting the pH of reaction mass to 8.5-9.5 with dilute hydrochloric acid.
xiv. addition of aq. calcium chloride solution.
xv. stirring till complete crystallization
xvi. filtration
xvii. Drying of wet cake at 45-60 "C for 10-20 hours to get pure Rosuvastatin calcium.
,&
f"'l !> f=% . ,- CI1 k P , 0 i 4 i" 3; &:c. .,
3 F I B
2 c>
2. The process as claimed in claim 1, where the solvent used in step (i) are selected from
methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene
glycol or a mixture thereof. 2 1 APR 2011
3. The process as claimed in claim 1, in which the strength of hydrochloric acid used in step
(ii) above was 0.2 N.
4. The process as claimed in claim 1, where the temperature in step (iii) & (iv) is 35-40 O C &
stirring time in step (iii) is 3-4 hours. Also the temperature of stirring in step (vii) is 25-35
"C & time of stirring is 3-6 hours & the temperature of heating in step no (ix) is 45-50 O C .
5. The process as claimed in claim 1,2 and 4 where if strength 1 quantity of hydrochloric acid
used is increased greater than 0.2 N, then the Rosuvastatin anti-isomer formed is increased
by 2 1.0 % by HPLC.
6. The process as claimed in claim 1, 3 and 4, where if the solvent used for reaction is an
aliphatic nitrile such as acetonitrile or propionitrile or mixture then the anti-isomer
impurity formation is increased by 2 1.0 % by HPLC.
7. The process as claimed in claims 5 and 6 simultaneously, if both strength of hydrochloric
acid is increased and solvent is an aliphatic nitrile; the Antiisomer formation is increased
by 1 3.0 % by HPLC.
8. A novel HPLC method of analysis which is capable of separating all major potential
impurities of Rosuvastatin Calcium.