Rosuvastatin Calcium

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

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Ca(C₂₂H₂₇FN₃O₆S)₂ ·1001.14

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)

CAS RN^®: 147098-20-2; UNII: 83MVU38M7Q.

Rosuvastatin (free acid)

C₂₂H₂₈FN₃O₆S 481.54

CAS RN^®: 287714-41-4, UNII: 413KH5ZJ73 (USP 1-Aug-2024)

1 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.

2 IDENTIFICATION

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A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197A or 197K  (USP 1-Aug-2024)

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B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. (USP 1-Aug-2024)

C. Identification Tests—General 〈191〉, Chemical Identification Tests, Calcium

Sample solution: 8 mg/mL of Rosuvastatin Calcium in a mixture of methanol and water (50:50)

Acceptance criteria: Meets the requirements

3 ASSAY

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3.1 Procedure

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

Solution A: Acetonitrile, 1% (v/v) aqueous trifluoroacetic acid, and water (29:1:70)

Solution B: Acetonitrile, 1% (v/v) aqueous trifluoroacetic acid, and water (75:1:24)

Mobile phase: See Table 1.

Table 1

Diluent: Acetonitrile and water (25:75)

System suitability stock solution A: 1 mg/mL of USP Rosuvastatin System Suitability Mixture RS in Diluent (USP 1-Aug-2024)

System suitability stock (USP 1-Aug-2024) solution B: (USP 1-Aug-2024)

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 (50:50)

System suitability stock (USP 1-Aug-2024) solution C: (USP 1-Aug-2024)

0.04 mg/mL of USP Rosuvastatin Related Compound C RS in a mixture of acetonitrile and water (50:50)

System suitability solution: 0.4 mg/mL of USP Rosuvastatin System Suitability Mixture RS, 5 µg/mL of USP Rosuvastatin Related Compound A RS, 5 µg/mL of USP Rosuvastatin Related Compound B RS, and 0.8 µg/mL of USP Rosuvastatin Related Compound C RS prepared as follows. Mix 10 mL of System suitability stock solution A, 0.5 mL of System suitability stock solution B, and 0.5 mL of System suitability stock solution C in a 25 mL-volumetric flask. Bring to volume with Diluent. (USP 1-Aug-2024)

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 (USP 1-Aug-2024) and Standard solution

[Note—The relative retention times for rosuvastatin related compound B and rosuvastatin related compound C are 2.2 and 2.6, respectively. (USP 1-Aug-2024) See Table 2 for the rest of (USP 1-Aug-2024) the relative retention times.]

Suitability requirements

Resolution: NLT 2.0 between rosuvastatin and rosuvastatin diastereomer  (USP 1-Aug-2024), System suitability solution (USP 1-Aug-2024)

Tailing factor: NMT 1.5  (USP 1-Aug-2024), Standard solution

Relative standard deviation: NMT 1.10%, Standard solution (USP 1-Aug-2024)

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of rosuvastatin calcium [Ca(C₂₂H₂₇FN₃O₆S)₂] in the portion of Rosuvastatin Calcium taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of rosuvastatin from the Sample solution

r_S = peak response of rosuvastatin from the Standard solution

C_S = concentration of USP Rosuvastatin Calcium RS in the Standard solution (mg/mL)

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

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

4 IMPURITIES

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4.1 Organic Impurities

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Solution A, Solution B, (USP 1-Aug-2024) Mobile phase, Diluent, System suitability stock solution A, System suitability stock solution B, System suitability stock solution C, (USP 1-Aug-2024) System suitability solution (USP 1-Aug-2024), Sample solution, and Chromatographic system (USP 1-Aug-2024): Proceed as directed in the Assay.

Standard solution: 1.4 μg/mL of USP Rosuvastatin Calcium RS in Diluent

Sensitivity solution: 0.35 μg/mL of USP Rosuvastatin Calcium RS from the Standard solution in Diluent

System suitability

Samples: System suitability solution, Standard solution, and Sensitivity solution

[Note—The relative retention times for rosuvastatin related compound B and rosuvastatin related compound C are 2.2 and 2.6, respectively.

See Table 2 for the rest of the relative retention times.]

Suitability requirements

Resolution: NLT 2.0 between rosuvastatin and rosuvastatin diastereomers, System suitability solution

Tailing factor: NMT 1.5, Standard solution

Relative standard deviation: NMT 5.0%, Standard solution

Signal-to-noise ratio: NLT 10, Sensitivity solution (USP 1-Aug-2024)

Analysis

Samples: Sample solution and Standard solution

Calculate the percentage of each impurity in the portion of Rosuvastatin Calcium taken:

Result = (r_U/r_S) × (C_S/C_U) × (1/F) × 100

r_U = peak response of each impurity from the Sample solution

r_S = peak response of rosuvastatin from the Standard solution

C_S = concentration of USP Rosuvastatin Calcium RS in the Standard solution (mg/mL)

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

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2.

The reporting threshold is 0.05%. (USP 1-Aug-2024)

Table 2

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 (S,2ZE,6E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl]-5-hydroxyhepta-2,6-dienoic acid.

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4.2 Enantiomeric Purity

Protect (USP 1-Aug-2024) all solutions containing rosuvastatin calcium and its related compounds from light. (USP 1-Aug-2024)

Mobile phase: Acetonitrile and 0.1% (v/v) trifluoroacetic acid in water (25:75)

Diluent: Acetonitrile and water (25:75)

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 〈621〉, 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

Run time: NLT 2.7 times the retention time of rosuvastatin (USP 1-Aug-2024)

System suitability

Samples: System suitability solution and Standard solution (USP 1-Aug-2024)

[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 rosuvastatin enantiomer and rosuvastatin (USP 1-Aug-2024), System suitability solution

Tailing factor: NMT 1.8, Standard solution

Relative standard deviation: NMT 5.0%, Standard solution (USP 1-Aug-2024)

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of rosuvastatin enantiomer in the portion of Rosuvastatin Calcium taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of rosuvastatin enantiomer from the Sample solution

r_S = peak response of rosuvastatin from the Standard solution

C_S = concentration of USP Rosuvastatin Calcium RS in the Standard solution (mg/mL)

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

Acceptance criteria: NMT 0.15%

Delete the following:

4.3 Limit of Chloride (USP 1-Aug-2024)

5 SPECIFIC TESTS

Water Determination 〈921〉, Method I, Method Ia or Method Ic: NMT 6%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers, protected from light. Store at controlled room temperature.

Change to read:

USP Reference Standards 〈11〉

USP Rosuvastatin Calcium 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(C₂₂H₂₇FN₃O₇S)₂ 1001.14

USP Rosuvastatin Related Compound A RS

Calcium (3R,5S,E)-7-{4-(4-fluorophenyl)-2-[(2-hydroxy-N,2-dimethylpropyl)sulfonamido (USP 1-Aug-2024)]-6-isopropylpyrimidin-5-yl}-3,5-dihydroxyhept-6-enoate salt (1:2).

Ca(C₂₅H₃₃FN₃O₈S)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-(N-methylmethylsulfonamido)pyrimidin-5-yl]-2-hydroxy-N-methylethylsulfonamido}-6-isopropylpyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate salt (1:2).

Ca(C₃₈H₄₅F₂N₆O₉S₂)₂ 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

USP Rosuvastatin System Suitability Mixture RS

Contains a mixture of the following 4 compounds. Other impurities may also be present.

Rosuvastatin calcium.

Rosuvastatin ketone: Calcium (R,E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl]-3-hydroxy-5-oxohept-6-enoate salt (1:2).

Ca(C₂₂H₂₅FN₃O₆S)₂ 997.11

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-methylmethanesulfonamide.

C₂₂H₂₆FN₃O₅S 463.52

Rosuvastatin diastereomers:

Calcium (3RS,5RS,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 1-Aug-2024)