Simvastatin Tablets

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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1 DEFINITION

Simvastatin Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of simvastatin (C₂₅H₃₈O₅).

2 IDENTIFICATION

A. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

B. The UV spectrum of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

3 ASSAY

3.1 PROCEDURE

Buffer solution: Dissolve 3.9 g of monobasic sodium phosphate in 900 mL of water. Adjust, if necessary, with either sodium hy droxide or phosphoric acid to a pH of 4.5. Dilute with water to 1000 mL and mix.

Mobile phase: Acetonitrile and Buffer solution (65:35)

Solution A: Add 3.0 mL of glacial acetic acid to 900 mL of water. Adjust with 5 N sodium hy droxide to a pH of 4.0 and dilute with water to 1 L. Diluent: Acetonitrile and Solution A (8:2)

Standard solution: 0.1 mg/mL of USP Simvastatin RS in Diluent

Sample solution: Nominally 0.1 mg/mL of simvastatin from Tablets in Diluent as follows. Crush NLT 20 Tablets into a fine powder and transfer the powder equivalent to 100 mg of simvastatin to a suitable volumetric flask. Add Diluent to fill 70% of the volume of the flask, and sonicate with intermittent swirling for 10 min. Equilibrate to room temperature and dilute with Diluent to volume. Centrifuge a portion of the mixture, and pass the clear supernatant through a filter of 0.45-µm pore size. Discard the first few milliliters of the filtrate.

3.1.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 238 nm. For Identification B, use a diode array detector in the range of 190–300 nm.

Column: 4.6-mm × 25-cm; 5-µm packing L1

Column temperature: 45° Flow rate: 1.5 mL/min

Injection volume: 10 µL

3.1.2 System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

3.1.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of simvastatin (C₂₅H₃₈O₅) in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak area of simvastatin from the Sample solution

r_S = peak area of simvastatin from the Standard solution

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

C_U = nominal concentration of simvastatin in the Sample solution (mg/mL)

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Change to read:

DISSOLUTION 〈711〉

Medium: Prepare a pH 7.0 buffer solution containing 0.5% sodium dodecyl sulfate in 0.01 M sodium phosphate as follows. Dissolve 30 g of sodium dodecyl sulfate and 8.28 g of monobasic sodium phosphate in 6000 mL of water and adjust with 50% (w/v) sodium hy droxide solution to a pH of 7.0; 900 mL.

Apparatus 2: 50 rpm

Time: 30 min

Prewashed manganese dioxide: Transfer 10 g of manganese dioxide to a suitable container, and treat as follows. Add 50 mL of Medium, and shake vigorously for 5 min. Centrifuge, decant the supernatant layer, and discard. Repeat twice, first with Medium and then with water. Dry the solid at 100° for 1 h before use.

Standard solution: USP Simvastatin RS in Medium. Transfer a portion of the solution to a centrifuge tube containing about 10 mg of Prewashed manganese dioxide per milliliter of transferred solution under test, and mix. Allow the mixture to stand for 30 min with occasional shaking, centrifuge, and use a portion of the clear supernatant. (ERR 1-Dec-2019)

Sample solution: Pass a portion of the solution under test through a suitable filter. Transfer a portion of the solution to a centrifuge tube containing about 10 mg of Prewashed manganese dioxide per milliliter of transferred solution under test, and mix. Allow the mixture to stand for 30 min with occasional shaking, centrifuge, and use a portion of the clear supernatant.

Instrumental conditions

Mode: UV

Analytical wavelengths: 247 and 257 nm

Blank: Prepare as directed for the Sample solution, except use the Medium.

Analysis: Calculate the percentage of the labeled amount of simvastatin (C₂₅H₃₈O₅) dissolved from the difference between the UV

absorbances at the wavelengths of maximum and minimum absorbances at about 247 and 257 nm, respectively, of the Sample solution, in comparison with the Standard solution.

Tolerances: NLT 75% (Q ) of the labeled amount of simvastatin (C₂₅H₃₈O₅) is dissolved.

UNIFORMITY OF DOSAGE UNITS 〈905〉: Meet the requirements

5 IMPURITIES

ORGANIC IMPURITIES

Solution A: Prepare a mixture of acetonitrile and dilute phosphoric acid (1 mL in 1 L of water) (45:55).

Solution B: Prepare a mixture of acetonitrile and dilute phosphoric acid (1 mL in 1 L of water) (90:10).

Mobile phase: See Table 1.

Table 1

Solution C: 1.4 g/L of monobasic potassium phosphate in water. Adjust with diluted ammonia solution to a pH of 7.0.

Diluent: Acetonitrile and Solution C (60:40)

System suitability stock solution: 0.2 mg/mL each of USP Simvastatin RS and USP Lovastatin RS in Diluent. Sonicate if necessary.

System suitability solution: 0.02 mg/mL each of USP Simvastatin RS and USP Lovastatin RS in Diluent from System suitability stock solution Standard solution: 7.5 µg/mL of USP Simvastatin RS and equivalent to 0.015 mg/mL of tenivastatin from USP Tenivastatin Calcium RS in Diluent

Sample solution: Nominally 1.5 mg/mL of simvastatin in Diluent prepared as follows. Transfer a suitable amount of powdered Tablets (NLT 20) to a volumetric flask. Add Diluent to fill 60% of the volume of the flask, and sonicate with intermittent swirling for 5 min. Dilute with Diluent to volume. Pass the solution through a filter of 0.45-µm pore size. Discard the first few milliliters of the filtrate.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 238 nm

Column: 4.6-mm × 15-cm; 5-µm packing L1

Temperatures

Autosampler: 10°

Column: 30°

Flow rate: 2 mL/min

Injection volume: 20 µL

Run time: NLT 3 times the retention time of simvastatin

System suitability

Samples: System suitability solution and Standard solution

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

Suitability requirements

Resolution: NLT 8.0 between simvastatin and lovastatin, System suitability solution

Tailing factor: NMT 1.5 for simvastatin, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of tenivastatin in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of tenivastatin from the Sample solution

r_S = peak response of tenivastatin from the Standard solution

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

C_U = nominal concentration of simvastatin in the Sample solution (mg/mL)

Calculate the percentage of any unspecified impurity in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of any unspecified impurity from the Sample solution

r_S = peak response of simvastatin from the Standard solution

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

C_U = nominal concentration of simvastatin in the Sample solution (mg/mL)

Acceptance criteria: See Table 2.

Table 2

^a (3R,5R)-7-{((1S,2S,6R,8S,8aR)-8-[(2,2)-Dimethylbutanoyl)oxy]-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl}-3,5-dihydroxyheptanoic acid.

^b Process impurity included in the table for identification purposes only. Process impurities are controlled in the drug substance, and are not to be reported or included in the total impurities for the drug product.

^c (S)-(1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-Hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2- methylbutanoate.

^d (R)-(1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-Hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2- methylbutanoate.

^e (1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-Hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2- dimethylbut-3enoate.

^f Methyl (3R,5R)-7-{(1S,2S,6R,8S,8aR)-8-[(2,2-dimethylbutanoyl)oxy]-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl}-3,5- dihydroxyheptanoate.

^g (1S,3R,8S,8aR)-8-{2-[(2R,4R)-4-Acetoxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2- dimethylbutanoate.

^h (1S,3R,7S,8S,8aR)-3,7-Dimethyl-8-{2-[(R)-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl}-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2- dimethylbutanoate.

ⁱ (3R,5R)-(2R,4R)-2-(2-{(1S,2S,6R,8S,8aR)-8-[(2,2-Dimethylbutanoyl)oxy]-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl}ethyl)-6- oxotetrahydro-2H-pyran-4-yl  7-{(1S,2S,6R,8S,8aR)-8-[(2,2-dimethylbutanoyl)oxy]-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl}-3,5- dihydroxyheptanoate.

^j Excluding lovastatin.

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight containers.

USP REFERENCE STANDARDS 〈11〉

USP Lovastatin RS

(S)-(1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-Hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl-2-methylbutanoate.

C₂₄H₃₆O₅         404.54

USP Simvastatin RS

USP Tenivastatin Calcium RS

Calcium  (3R,5R)-7-{(1S,2S,6R,8S,8aR)-8-[(2,2-dimethylbutanoyl)oxy]-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl}-3,5- dihydroxyheptanoate (1:2) monohydrate.

C₅₀H₇₈CaO₁₂ · H₂O    929.24