Simvastatin
(sim'' va stat' in).
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418.57Butanoic acid, 2,2-dimethyl-, 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl ester, [1S-[1
,3,7
,8(2S*,4S*),8a]].
2,2-Dimethylbutyric acid, 8-ester with (4R,6R)-6-2-[(1S,2S,6R,8S,8
R)-1,2,6,7,8,8a-hexahydro-8-hydroxy-2,6-dimethyl-1-naphthyl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one
[79902-63-9].» Simvastatin contains not less than 98.0 percent and not more than 102.0 percent of C25H38O5, calculated on the dried basis. It may contain a suitable antioxidant.
Packaging and storage—
Preserve in well-closed containers. Store between 15
and 30, or under refrigeration.
and 30, or under refrigeration.
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Identification—
B:
The retention time of the major peak in the chromatogram of the Assay preparation corresponds to that in the chromatogram of the Standard preparation, as obtained in the Assay.
Loss on drying 
731
—
Dry it in vacuum at 60 for 3 hours: it loses not more than 0.5% of its weight.
731—
Dry it in vacuum at 60 for 3 hours: it loses not more than 0.5% of its weight.
Residue on ignition 281:
not more than 0.1%.
281:
not more than 0.1%.
Heavy metals, Method II 231:
0.002%.
231:
0.002%.
Chromatographic purity—
[note—The Simvastatin solutions are stable for up to 3 days when stored at 4. Without refrigeration, they should be injected immediately after preparation. ]
. Without refrigeration, they should be injected immediately after preparation. ]
Mobile phase, Diluent, and Chromatographic system—
Proceed as directed in the Assay.
Test solution—
Use the Assay preparation.
Procedure—
Inject about 5 µL of the Test solution into the chromatograph, record the chromatogram, identify the specified impurities listed in Table 1, and measure the areas for all the peaks. Calculate the percentage of each impurity in the portion of Simvastatin taken by the formula:
100(ri / rs)
in which ri is the peak area for each impurity; and rs is the sum of the areas of all the peaks. Reporting level for impurities is 0.05%.
Table 1
| Name | Relative Retention Time | Limit % |
|---|---|---|
| Simvastatin hydroxyacid1 | 0.45 | 0.4 |
| Epilovastatin2 and Lovastatin | 0.60 | 1.03 |
| Methylene simvastatin4 | 0.80 | 0.4 |
| Simvastatin | 1.0 | n/a |
| Acetyl simvastatin5 | 2.38 | 0.4 |
| Anhydro simvastatin6 | 2.42 | 0.4 |
| Simvastatin dimer7 | 3.80 | 0.4 |
| Any other individual impurity | — | 0.1 |
| Total impurities other than lovastatin and epilovastatin | — | 1.0 |
|
1
(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.
2
(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 (2R)-2-methylbutanoate.
3
If present, lovastatin and epilovastatin may not be completely resolved by the method. These peaks are integrated together to determine conformance.
4
(1S,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-3-enoate.
5
(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-(Acetyloxy)-6-oxotetrahydro-2H-pyran-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2-dimethylbutanoate.
6
(1S,3R,7S,8S,8aR)-3,7-Dimethyl-8-[2-[(2R)-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2-dimethylbutanoate.
7
(2R,4R)-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 (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.
|
||
Assay—
[note—The Simvastatin solutions are stable for up to 3 days when stored at 4. Without refrigeration, they should be injected immediately after preparation. ]
. Without refrigeration, they should be injected immediately after preparation. ]
Dilute phosphoric acid—
Transfer 1 mL of phosphoric acid to a 1-L volumetric flask, and dilute with water to volume.
Solution A—
Prepare a mixture of acetonitrile and Dilute phosphoric acid (50:50).
Solution B—
Transfer 1 mL of phosphoric acid to a 1-L volumetric flask, and dilute with acetonitrile to volume.
Mobile phase—
Use variable mixtures of Solution A and Solution B, as directed for Chromatographic system. Make adjustments if necessary (see System Suitability under Chromatography 621).
621).
Buffer solution—
Prepare a solution containing 1.4 g of monobasic potassium phosphate per L, and adjust with phosphoric acid to a pH of 4.0.
Diluent—
Prepare a mixture of acetonitrile and Buffer solution (3:2).
System suitability preparation—
Dissolve accurately weighed quantities of USP Simvastatin RS and USP Lovastatin RS in Diluent, and dilute quantitatively, and stepwise if necessary, with Diluent to obtain a solution having known concentrations of about 1.5 mg per mL of USP Simvastatin RS and 0.015 mg per mL of USP Lovastatin RS.
Standard preparation—
Dissolve an accurately weighed quantity of USP Simvastatin RS in Diluent to obtain a solution having a known concentration of about 1.5 mg per mL.
Assay preparation—
Transfer about 75 mg of Simvastatin, accurately weighed, to a 50-mL volumetric flask, dissolve in and dilute with Diluent to volume, and mix.
Chromatographic system (see Chromatography 621—
The liquid chromatograph is equipped with a 238-nm detector and a 4.6- × 33-mm column that contains packing L1. The flow rate is about 3.0 mL per minute. The chromatograph is programmed as follows.
Chromatograph the System suitability preparation, and record the peak responses as directed for Procedure: the relative retention times are about 0.60 for lovastatin and 1.0 for simvastatin; and the resolution, R, between simvastatin and lovastatin is greater than 3. Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the relative standard deviation for replicate injections is not more than 1.0%.
621—
The liquid chromatograph is equipped with a 238-nm detector and a 4.6- × 33-mm column that contains packing L1. The flow rate is about 3.0 mL per minute. The chromatograph is programmed as follows.
| Time (minutes) |
Solution A
(%) |
Solution B
(%) |
Elution |
|---|---|---|---|
| 0–4.5 | 100 | 0 | isocratic |
| 4.5–4.6 | 100®95 | 0®5 | linear gradient |
| 4.6–8.0 | 95®25 | 5®75 | linear gradient |
| 8.0–11.5 | 25 | 75 | isocratic |
| 11.5–11.6 | 25®100 | 75®0 | linear gradient |
| 11.6–13 | 100 | 0 | re-equilibration |
Procedure—
Separately inject equal volumes (about 5 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the areas for the major peaks. Calculate the quantity, in mg, of C25H38O5 in the portion of Simvastatin taken by the formula:
VC(rU / rS)
in which V is the volume, in mL, of the Assay preparation; C is the concentration, in mg per mL, of USP Simvastatin RS in the Standard preparation; and rU and rS are the responses of the simvastatin peak obtained from the Assay preparation and the Standard preparation, respectively.
Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Elena Gonikberg, Ph.D.
Principal Scientific Liaison 1-301-816-8251 |
(SM32010) Monographs - Small Molecules 3 |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 4639
Pharmacopeial Forum: Volume No. 33(5) Page 948