240268104 Rosuvastatin EP MonographRosuvastatin EP Monograp

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48 © Pharmeuropa 25.3 I

July

2013

Reference solution (e).

In

order to prepare impurity C

in

situ, heat 0.25 g of the substance to be

examined at 50 oc for 7 days in amber glassware with a porous coveri57J. Dissolve 50 mg in 11 ml

of acetonitrile for chromatography

R

add 3.0

m l of

reference solution c) and 1.0

ml of

reference

solution d). Dilute to 50.0 ml with water for chromatography R.

Column:

- size:

I

0.15

m,

0 = 3.0 mm;

- stationary phase: base-deactivated end-capped octadecylsilyl silica gel for chromatography R

3

1Jm)I5BJ;

- temperature: 40 oc

Mobile phase:

- mobile phase A: 1 per cent

\ IN

solution of trifluoroacetic acid R acetonitrile for

chromatography

R

water for chromatography R

1

:29:70

\I

\.IN);

- mobile phase 8: 1 per cent

\ IN

solution of trifluoroacetic acid R water for chromatography R

acetonitrile for chromatography R

1

:24:75

\I

\.IN);

Time

min)

0-30

30-50

50-60

60- 75

Flow rate: 0.75 ml/min.

Detection: spectrophotometer at 242 nm.

Mobile phase

A

per

cent

11/V

100

100--+ 60

60--+ 0

0

lr,jection: 10

iJL

of the test solution and reference solutions b) and e).

Mobile phase

B

per

cent

11/V

0

0--+ 40

40--+ 100

100

Identification

of

mpurities: use the chromatogram obtained with reference solution e) to identify

the peaks due to impurities A, B and C.

Relative retention with reference to rosuvastatin retention time =about 25 min):

impurity A = about 0.9; impurity B = about

1.1

; impurity C = about 1.5.

System suitability: reference solution e):

- resolution: minimum 2.0 between the peaks due to rosuvastatin and impurity B.

Calculation

of

percentage contents:

- correction factor: multiply the peak area of impurity C by 2.1 ;

- for each impurity, use the concentration of rosuvastatin in reference solution b).

Limits:

- impurity C: maximum 0.6 per cent;

- impurity

8:

maximum 0.5 per cent;

- impurity A: maximum 0.2 per cent;

- unspecified impurities: for each impurity, maximum 0.10 per cent;

- total: maximum 1.2 per cent;

- reporting threshold: 0.05 per cent.

57) Place a small vial containing the substance inside a small beaker and then cover the beaker with filter paper secured

with an elastic band.

58) lnertsil ODS-3 is suitable.

PAIPHIExp P41T

11) 36

ANP


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©

Pharmeuropa 25.31 July 2013 149

The following chromatogram is shown for information but will not be published in the European

Pharmacopoeia.

2

3

7

6

5

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I

1

2 3

4

5 ro oo ~

1. impurity A

3.

impurity B 5. impurity E 7. impurity F

2. rosuvastatin

4.

impurity C 6. impurity J

Figure 2631.-1. Chromatogram for the test for related substances

of

rosuvastatin calcium:

reference solution e) spiked with impurities E, F and J

Enantiomeric purity. Liquid chromatography 2.2.29). Prepare the solutions immediately before

use and protect them from light throughout the test.

Solvent mixture: acetonitrile for chromatography

R,

water for chromatography R

25:75 11/V).

Test solution. Dissolve 25.0 mg of the substance to be examined in 6 ml of acetonitrile for

chromatography

Rand dilute to 25.0 ml with

water for chromatography R.

Reference solution a). Dilute 1.0

ml

of the test solution to 100.0 ml with the solvent mixture.

Dilute

1.0 ml

of this solution to

10.0 ml

with the solvent mixture.

Reference solution b).

Dissolve 5 mg of

rosuvastatin impurity

G

CRS in

a mixture of 12

ml

of acetonitrile for chromatography Rand 10 ml of water for chromatography R with the aid of

ultrasound and dilute to 50.0

ml

with

water for chromatography R.

Reference solution c).

To

25 mg of the substance to be examined add 1.0

ml

of reference

solution b), 6 ml of acetonitrile for chromatography Rand dissolve with the aid of ultrasound;

dilute to 25

ml

with

water for chromatography

R.

Column:

- size: I=

0.15 m, 0 =4.6 mm;

- stationary phase: silica gel OJ for chiral separations R

5

1Jm)I

59

J;

- temperature:

35

oc

Mobile phase: acetonitrile for chromatography R, 0.1

per cent

\ IN

solution

of trifluoroacetic

acid R

25:75 11/V).

Flow rate:

0.5

ml/min

59) Chiralcel OJ-RH

is

suitable.

PA/PH/Exp. P4/T 11) 6 ANP


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150 © Pharmeuropa 25.3 IJuly 2013

Detection: spectrophotometer at 254 nm.

lr jection: 10

iJL

of the test solution and reference solutions a) and c).

Run time: 3 times the retention time of rosuvastatin.

Identification

of

mpurities: use the chromatogram supplied with rosuvastatin impuri ty G CRS and

the chromatogram obtained with reference solution c) to identify the peak due to impurity G.

Relative retention with reference to rosuvastatin retention

time

about 25 min): impurity G

about

0.9.

System suitability: reference solution c):

- resolution: minimum 1.5 between the peaks due to impurity G and rosuvastatin.

Calculation

of

percentage content:

- use the concentration

of

rosuvastatin

in

reference solution a).

Limit:

- impurity G: maximum 0 1 per cent.

The following chromatogram is shown for information but will not be published in the European

Pharmacopoeia.

2

A A l

\

1

/ '

I

I I I I I I I

1

2

3

4 5

6

7

1 impurity G

2

rosuvastatin

Figure 2631.-2. Chromatogram for the test for enantiomeric purity of rosuvastatin calcium:

reference solution c)

Chlorides: maximum 0.2 per cent.

Dissolve 0.15 g in 60

ml

of water R by heating to boiling while stirring. Add 4

ml

of dilute nitric

acid

R,

allow

to

cool to room temperature and titrate with 0.01 M silver nitrate determining the

end-point potentiometrically 2.2.20) using a silver indicator electrode and a silver-silver chloride

reference electrode.

1

0

ml of 0 01 M silver nitrate is equivalent to 0.3545 mg of Cl.

Water

2.5.32): maximum 6.0 per cent, determined on 20.0 mg.

PAIPHIExp. P4 T 11) 36 ANP

I

min


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5

ASSAY

Liquid chromatography 2.2.29) as described in the test for related substances with the following

modification.

lr,jection: test solution and reference solution a).

Calculate the percentage content of C

H

54

CaF

N

6

0

12

S

taking into account the assigned content

of

rosuvastatin calcium CRS.

STORAGE

In

an airtight container protected from light at a temperature of 2 octo 8 oc.

IMPURITIES

Specified impurities: A, B C G.

Other detectable impurities

the following substances would, if present at a sufficient level,

be detected by one or other of the tests in the monograph. They are limited by the general

acceptance criterion for other/unspecified impurities and/or by the general monograph

Substances for pharmaceutical use 2034).

It

is

therefore not necessary to identify these

impurities for demonstration

of

compliance. See also

5

10.

Control

of

mpurities in substances for

pharmaceutical use): 0 E

F

H I

J

F

A. 3R

5S, 6E)-7 -[ 4- 4-

fl

uorophenyl )-2-[[ 2-hyd roxy-2-methyl propyl )sulfonyl] methyl )ami no ]-6-

propan-2-yl )pyri midi n-5-yl]-3, 5-d hyd roxyhept -6-enoic acid,

F

and enantiomer

B 3RS,5RS,6E)-7 -[ 4- 4-fluorophenyl)-2-[methyl methylsulfonyl)amino -6- propan-2-

yl )pyri midi n-5-yl]-3, 5-d i hyd roxyhept -6-eno c acid,

F

C. 3R 6E)-7 -[ 4- 4- fluorophenyl )-2-[ methyl methylsu fonyl )ami no ]-6- pro pan-2-yl )pyri midi n-5-yl]-

3-hydroxy-5-oxohept-6-enoic acid,

PAIPHIExp. P4 T 11) 36 ANP


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152 Pharmeuropa 25.3

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July 2013

F

D N-[4- 4-fluorophenyi)-5-[ E)-2-[ 2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethenyl]-6-

propan-2-yl)pyrimidin-2-yi]-N-methylmethanesulfonamide,

F

E 3R,5S,6E)-7 -[ 4- 4-fluorophenyl)-2-[ [2-[ 4- 4-fluorophenyl)-2-[methyl methylsulfonyl)amino -6-

propan-2-yl)pyrimidin-5-yl]-2-hydroxyethyl]sulfonyl) methyl)amino]-6- propan-2-yl)pyrimidin-

5-yl]-3,5-dihydroxyhept-6-enoic acid,

F

F 1 1-dimethylethyl [ 4R,6S)-6-[ E)-2-[4- 4-fluorophenyl)-2-[methyl methylsulfonyl)amino]-6-

propan-2-yl)pyrimidin-5-yl]ethenyl]-2,2-dimethyl-1

,3-dioxan-4-yl]acetate,

F

·· H

OH

G. 3S,5R,6E)-7 -[ 4- 4-fluorophenyl)-2-[methyl methylsulfonyl)amino -6- propan-2-yl)pyrimid n-5-

yl]-3, 5-d ihyd roxyhept-6-eno c acid,

F

·· OH

H

and epi

mer

at c·

H

3R 5R S)-5-[8-

fl

uoro-2-[ methyl methylsu fonyl )ami no ]-4- propan-2-yl )-5, 6-

dihydrobenzo[h]quinazolin-6-yl]-3,5-dihydroxypentanoic acid,



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Pharmeuropa 25.31 July 2013

F

· · H

O

and epim rat

·

I 3S,5RS)-5-[8-fluoro-2-[methyl methylsulfonyl)amino]-4- propan-2-yl)-5,6-

dihydrobenzo[h]quinazolin-6-yl]-3,5-dihydroxypentanoic acid,

F

153

J 3R,5S,6E)-7 -[ 4- 4-fluorophenyi)-2-[ [ E)-2-[4- 4-fluorophenyl)-2-[methyl methylsulfon

yl)amino]-6- propan-2-yl)pyrimidin-5-yl]ethenyl]sulfonyl) methyl)amino]-6- propan-2-yl)pyri

m d in-5-yl]-3, 5-d ihyd roxyhept -6-e noic acid.


240268104 Rosuvastatin EP MonographRosuvastatin EP Monograp

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