Rosuvastatin EP Monograph

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Reference: PNPH/Exp. P4/T (11) 36 ANP XXXX:2631

ROSUVASTATIN CALCIUM

Rosuvastatinum calcicum F

C44H54CaF 2N6012S2 [14 7098-20-2]

M, 1001

DEFINITION Ca lei um bis[ (3R ,5 S, 6E)-7 -[4-( 4-fl uorophenyl )-2-[ methyl( methylsu lfonyl )ami no ]-6-(propan-2yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate]. Content: 97.0 per cent to 102.0 per cent (anhydrous substance).

CHARACTERS Appearance: white or almost white, hygroscopic powder. Solubility: slightly soluble in water, freely soluble in methylene chloride, practically insoluble in anhydrous ethanol.

IDENTIFICATION

A. Infrared absorption spectrophotometry (2.2.24). Comparison: rosuvastatin calcium CRS.

B. Enantiomeric purity (see Tests). Results: the principal peak in the chromatogram obtained with the test solution is similar in retention time to the principal peak in the chromatogram obtained with reference solution (c).

C. It gives reaction (b) of calcium (2.3.1). TESTS Related substances. Liquid chromatography (2.2.29). Carry out the test protected from light. Test solution. Dissolve 35.0 mg of the substance to be examined in 12 ml of acetonitrile for chromatography Rand dilute to 50.0 ml with water for chromatography R. Reference solution (a). Dissolve 35.0 mg of rosuvastatin calcium CRS in 12 ml of acetonitrile for chromatography Rand dilute to 50.0 ml with water for chromatography R. Reference solution (b). To 1.0 ml of the test solution add 24 ml of acetonitrile for chromatography Rand dilute to 100.0 ml with water for chromatography R. To 2.0 ml of this solution add 2 ml of acetonitrile for chromatography Rand dilute to 10.0 ml with water for chromatography R. Reference solution (c). In order to prepare impurity Bin situ, dissolve 10 mg of the substance to be examined in 10 ml of a 1 per cent \IN solution of trifluoroacetic acid R in acetonitrile for chromatography R. Stopper and heat at 40 oc for 1 h. Cool, add 20 ml of water for chromatography Rand adjust to pH 6-8 with a 42 g/L solution of sodium hydroxide R. Dilute to 50 ml with water for chromatography R. Reference solution (a). Dissolve 5 mg of rosuvastatin impurity A CRS in 10 ml of acetonitrile for chromatography Rand dilute to 20.0 ml with water for chromatography R.

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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 ml 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

Mobile phase A

Mobile phase B (per cent 11/V)

(min)

(per cent 11/V)

0-30

100

0

30-50

100--+ 60

0--+ 40

50-60

60--+ 0

40--+ 100

60- 75

0

100

Flow rate: 0.75 ml/min. Detection: spectrophotometer at 242 nm. lr,jection: 10 iJL of the test solution and reference solutions (b) and (e). Identification of impurities: 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.

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The following chromatogram is shown for information but will not be published in the European Pharmacopoeia. 2

4

3

5

I

I

I

I

0

I

I

I

I

I

I

10

I

I

20

I

I

I

I

I

30

I

I

40

I

I

I

I

I

50

1. impurity A

3. impurity B

5. impurity E

2. rosuvastatin

4. impurity C

6. impurity J

7

6

I

I

I

I

I

~

I

I

I

ro

I

I

I

7. impurity F

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)I59J; - 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.

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I

oo

I

m~

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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 impurities: use the chromatogram supplied with rosuvastatin impurity 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 I

0

A.l

1

\

~

/"'

I

I

I

I

I

I

I

10

20

30

40

50

60

70

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.

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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 C44 H54 CaF 2 N6 0 12 S 2 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 impurities 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 ihyd roxyhept -6-enoic acid,

F

and enantiomer

B. (3RS,5RS,6E)-7 -[ 4-( 4-fluorophenyl)-2-[methyl( methylsulfonyl)amino ]-6-(propan-2yl )pyri midi n-5-yl]-3, 5-d ihyd roxyhept -6-eno ic acid,

F

C. (3R ,6E)-7 -[ 4-( 4-fl uorophenyl )-2-[ methyl( methylsu lfonyl )ami no ]-6-(pro pan-2-yl )pyri midi n-5-yl]3-hydroxy-5-oxohept-6-enoic acid,

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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)pyrimidin5-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 in-5yl]-3, 5-d ihyd roxyhept-6-eno ic acid, F

·· OH H and epimer at

c·

H. (3R ,5R S)-5-[8-fl uoro-2-[ methyl( methylsu lfonyl )ami no ]-4-(propan-2-yl )-5, 6dihydrobenzo[h]quinazolin-6-yl]-3,5-dihydroxypentanoic acid,

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F

· ·H

OH and epi mer at

c·

I. (3S,5RS)-5-[8-fluoro-2-[methyl(methylsulfonyl)amino]-4-(propan-2-yl)-5,6dihydrobenzo[h]quinazolin-6-yl]-3,5-dihydroxypentanoic acid, F

J. (3R,5S,6E)-7 -[ 4-( 4-fluorophenyi)-2-[([(E)-2-[4-( 4-fluorophenyl)-2-[methyl( methylsulfonyl)amino]-6-(propan-2-yl)pyrimidin-5-yl]ethenyl]sulfonyl)(methyl)amino]-6-(propan-2-yl)pyrim id in-5-yl]-3, 5-d ihyd roxyhept -6-e noic acid.

PA/PH/Exp. P4/T (11) 36 ANP