This post contains Rosuvastatin Calcium USP Monograph USP 44 - NF39, Definition, Identification, Assay, Impurities, Specific Tests, Additional Requirements.

Rosuvastatin Calcium USP

Ca(C22H27FN3O6S)2

6-Heptenoic acid, 7-[4-(4-fluorophenyl)-6-(1-methylethyl)- 2-[methyl methylsulfonyl)amino]-5-pyrimidinyl]- 3,5-dihydroxy-, calcium salt (2:1), (3R,5S,6E); [S-[R*,S*-(E)]]-7-[4-(4-Fluorophenyl)-6-(1-methylethyl)- 2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]-3,5-dihydroxy-6-heptenoic acid, calcium salt (2:1); Calcium (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate salt (1:2) [147098-20-2].

DEFINITION

Rosuvastatin Calcium contains NLT 97.0% and NMT 103.0% of rosuvastatin calcium [Ca(C22H27FN3O6S)2], calculated on the anhydrous and solvent-free basis.

IDENTIFICATION 

Change to read:

A. ▲SPECTROSCOPIC IDENTIFICATION TESTS 97.0%, Infrared Spectroscopy: 197A OR 197K▲ (CN 1-May-2020) or (197A)

B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the test for Enantiomeric Purity.

C. IDENTIFICATION TESTS—GENERAL (191), Chemical Identification Tests, Calcium

Sample solution: 8 mg/mL of Rosuvastatin Calcium in a mixture of methanol and water (1:1)

Acceptance criteria: Meets the requirements

ASSAY

PROCEDURE

Protect all solutions containing rosuvastatin calcium and its related compounds from light.

Solution A: Acetonitrile, 1% (v/v) aqueous trifluoroacetic acid, and water (290:10:700)

Solution B: Acetonitrile, 1% (v/v) aqueous trifluoroacetic acid, and water (750:10:240)

Mobile phase: See Table 1.

Time (min)

Solution A (%)

Solution B (%)

0

100

0

30

100

0

50

60

40

60

0

100

70

0

100

71

100

0

80

100

0


Diluent: Acetonitrile and water (25:75)

System suitability solution A: Dissolve 10 mg of Rosuvastatin Calcium in 10 mL of 1% trifluoroacetic acid in ethyl acetate. Heat at 40° for 1 h. Cool, and transfer to a separatory funnel. Add 2 mL of 1 M sodium hydroxide, and shake for 30 s. Allow the layers to separate, and discard the lower aqueous layer. Add 2 mL of water, and shake for 10 s. Allow the layers to separate, and discard the aqueous layer. Transfer 2 mL of the retained organic layer to a 50-mL standard flask, add 12 mL of acetonitrile, and dilute with water to volume. This solution contains predominantly rosuvastatin lactone.

System suitability solution B: Dissolve 10 mg of Rosuvastatin Calcium in a 50-mL volumetric flask in 10 mL of 1% trifluoroacetic acid in acetonitrile. Stopper, and heat at 40° for 1 h. Cool, add 20 mL of water, and neutralize with 1 M sodium hydroxide to a pH of 6–8. Dilute with water to volume. This solution contains predominantly rosuvastatin diastereomers.

System suitability solution C: 0.25 mg/mL each of USP Rosuvastatin Related Compound A RS and USP Rosuvastatin Related Compound B RS in a mixture of acetonitrile and water (1:1)

System suitability solution D: 0.04 mg/mL of USP

Rosuvastatin Related Compound C RS in a mixture of acetonitrile and water (1:1)

System suitability solution E: Heat 250 mg of Rosuvastatin Calcium at 50° for 7 days in suitable glassware with a porous cover. Dissolve 50 mg of the heated rosuvastatin calcium in 11 mL of acetonitrile in a 50-mL standard flask. Add 5 mL of System suitability solution A, 3 mL of System suitability solution B, 1 mL of System suitability solution C, and 1 mL of System suitability solution D. Dilute with water to volume.

Standard solution: 0.7 mg/mL of USP Rosuvastatin

Calcium RS in Diluent

Sample solution: 0.7 mg/mL of Rosuvastatin Calcium in

Diluent

Chromatographic system

(See Chromatography (621), System Suitability.) 

Mode: LC

Detector: UV 242 nm

Column: 3.0-mm × 15-cm; 3-µm packing L1 Column temperature: 40°

Flow rate: 0.75 mL/min

Injection volume: 10 µL

System suitability

Samples: System suitability solution E and Standard solution

[NOTE—See Table 2 for relative retention times.] Suitability requirements

Resolution: NLT 2.0 between the rosuvastatin and rosuvastatin diastereomer peaks, System suitability solution E

Tailing factor: NMT 1.5 for the rosuvastatin peak,

Standard solution 

Analysis

Samples: Standard solution and Sample solution Calculate the percentage of rosuvastatin calcium

[Ca(C22H27FN3O6S)2] in the portion of Rosuvastatin Calcium taken:

Result = (rU / rS) × (CS  / CU) × 100

rU        = peak response of rosuvastatin from the Sample solution

rS        = peak response of rosuvastatin from the Standard solution

cS        = concentration of USP Rosuvastatin Calcium RS in the Standard solution 

            (mg/mL)

cU        = concentration of Rosuvastatin Calcium in the Sample solution (mg/mL)


Acceptance criteria: 97.0%–103.0% on the anhydrous and solvent-free basis 

IMPURITIES

ORGANIC IMPURITIES

Protect all solutions containing rosuvastatin calcium and its related compounds from light.

Mobile phase, Diluent, System suitability solution E,

Sample solution, Chromatographic system, and System suitability: Proceed as directed in the Assay.

Standard solution: 0.0014 mg/mL of USP Rosuvastatin

Calcium RS in Diluent

Analysis

Samples: Sample solution and Standard solution Calculate the percentage of each impurity in the portion of

Rosuvastatin Calcium taken:


Result = (rU / rS) × (CS  / CU(1/F) × 100

rU        = peak response of each impurity from the Sample solution
rS        = peak response of rosuvastatin from the Standard solution
cS        = concentration of USP Rosuvastatin Calcium RS in the Standard solution                  (mg/mL)
cU        = concentration of Rosuvastatin Calcium in the Sample solution (mg/mL)
f          = relative response factor (see Table 2)

Acceptance criteria: See Table 2. Disregard peaks less than 0.05%.

Name

Relative Retention Time

Relative Response Factor

Acceptance Criteria, NMT (%)

Rosuvastatin related compound A

0.9

1.00

0.2

Rosuvastatin

1.0

1.00

Rosuvastatin diastereomersa

1.1

1.00

0.5

Rosuvastatin ketoneb

1.5

0.71

0.8

Rosuvastatin lactonec

1.7

1.00

0.15

Rosuvastatin related compound Bd

2.2

1.00

Rosuvastatin dehydro analoge

1.8

1.00

0.15

Rosuvastatin related compound Cd

2.6

1.00

Any unspecified impurity

1.00

0.10

Total impurities

1.5


a (3RS,5RS,E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid.
b (R,E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido) pyrimidin-5-yl]-3-hydroxy-5-oxohept-6-enoic acid.
c N-[4-(4-Fluorophenyl)-5-{(E)-2-[(2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]vinyl}-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide.
d Classified as any unspecified impurity.
e (S,2ZE,6E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl]-5-hydroxyhepta-2,6-dienoic acid. 

ENANTIOMERIC PURITY

Prepare all solutions containing rosuvastatin calcium and its
related compounds in amber glassware.
Mobile phase: Acetonitrile and 0.1% (v/v) trifluoroacetic
acid in water (25:75)
Diluent: Prepare as directed in the Assay.
System suitability solution: 1 mg/mL of USP Rosuvastatin
Calcium RS and 0.004 mg/mL of USP Rosuvastatin Enantiomer RS in Diluent
Standard solution: 0.005 mg/mL of USP Rosuvastatin
Calcium RS in Diluent
Sample solution: 1 mg/mL of Rosuvastatin Calcium in
Diluent
Chromatographic system
(See Chromatography á621ñ, System Suitability.) Mode: LC
Detector: UV 242 nm
Column: 4.6-mm × 15-cm; 5-µm packing L107 Column temperature: 35°
Flow rate: 0.5 mL/min
Injection volume: 10 µL
System suitability
Sample: System suitability solution
[NOTE—The relative retention times for rosuvastatin
enantiomer and rosuvastatin are about 0.9 and 1.0,
respectively.]
Suitability requirements
Resolution: NLT 1.5 between the rosuvastatin
enantiomer and rosuvastatin peaks
Tailing factor: NMT 1.8 for the rosuvastatin peak
Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of rosuvastatin enantiomer in the
portion of Rosuvastatin Calcium taken:

Result = (rU / rS) × (CS  / CU) × 100

rU        = peak response of rosuvastatin enantiomer from the Sample solution

rS        = peak response of rosuvastatin from the Standard solution

cS        concentration of USP Rosuvastatin Calcium RS in the Standard solution 

            (mg/mL)

cU        = concentration of Rosuvastatin Calcium in the Sample solution (mg/mL)

Acceptance criteria: NMT 0.15%

• LIMIT OF CHLORIDE

Sample: 150 mg of Rosuvastatin Calcium

Titrimetric system

(See Titrimetry á541ñ.)

Mode: Direct titration

Titrant: 0.01 M silver nitrate

Endpoint detection: Potentiometric

Blank: 60 mL of water and 5 mL of 10% (v/v) aqueous

nitric acid

Analysis: Dissolve the Sample in 60 mL of water, and add

5 mL of 10% (v/v) aqueous nitric acid. Titrate with Titrant.

Calculate the percentage of chloride in the portion of

Rosuvastatin Calcium taken:

Result  = {[(VS − VB) × M × F]/W} × 100

VS            = Titrant volume consumed by the Sample (mL) 

VB                    = Titrant volume consumed by the Blank (mL) 

M         = actual molarity of the Titrant (mmol/mL)

F          = equivalency factor, 35.45 mg/mmol

W         = Sample weight (mg)

Acceptance criteria: NMT 0.2%

SPECIFIC TESTS

WATER DETERMINATION (921), Method I, Method I, or Method Ic: NMT 6%

ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in well-closed containers, protected from light. Store at controlled room temperature.

USP REFERENCE STANDARDS 

USP Rosuvastatin Calcium RS

USP Rosuvastatin Enantiomer RS

USP Rosuvastatin Enantiomer RS

Calcium (3S,5R,E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-

(N-methylmethylsulfonamido)pyrimidin-5-yl]-

3,5-dihydroxyhept-6-enoate salt (1:2).

Ca(C22H27FN3O6S)2 1001.14

USP Rosuvastatin Related Compound A RS

Calcium (3R,5S,E)-7-{4-(4-fluorophenyl)-2-[(2-hydroxy-

N,2-dimethylpropyl)sulfonamide]-

6-isopropylpyrimidin-5-yl}-3,5-dihydroxyhept-6-enoate

salt (1:2).

Ca(C25H33FN3O7S)2 1117.30

USP Rosuvastatin Related Compound B RS

Calcium (3R,5S,E)-7-(4-(4-fluorophenyl)-2-{2-[4-(4-

fluorophenyl)-6-isopropyl-2-(Nmethylmethylsulfonamido)

pyrimidin-5-yl]-2-hydroxy-

N-methylethylsulfonamido}-6-isopropylpyrimidin-5-yl)-

3,5-dihydroxyhept-6-enoate salt (1:2).

Ca(C38H45F2N6O9S2)1703.93

USP Rosuvastatin Related Compound C RS

tert-Butyl 2-[(4R,6S)-6-{(E)-2-[4-(4-fluorophenyl)-6- isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5- yl]vinyl}-2,2-dimethyl-1,3-dioxan-4-yl]acetate. C29H40FN3O6S 577.71