Edition: BP 2025 (Ph. Eur. 11.6 update)
Action and use
HMG Co-A reductase inhibitor; lipid-regulating drug.
DEFINITION
Simvastatin Oral Suspension is a suspension of Simvastatin in a suitable flavoured vehicle.
PRODUCTION
A suitable dissolution test is carried out to demonstrate the appropriate release of Simvastatin. The dissolution profile reflects the in vivo performance which in turn is compatible with the dosage schedule recommended by the manufacturer.
The oral suspension complies with the requirements stated under Oral Liquids and with the following requirements.
Content of simvastatin, C25H38O5
90.0 to 105.0% of the stated amount.
IDENTIFICATION
A. Carry out the method for thin-layer chromatography, Appendix III A, using the following solutions in dichloromethane.
(1) Shake a quantity of the oral suspension containing 25 mg of Simvastatin with 10 mL of dichloromethane for 10 minutes. Allow to separate and use the lower layer.
(2) 0.25% w/v of simvastatin BPCRS.
CHROMATOGRAPHIC CONDITIONS
(a) Use as the coating silica gel F254 (Merck silica gel 60 F254 plates are suitable).
(b) Use the mobile phase as described below.
(c) Apply 5 µL of each solution.
(d) Develop the plate to 15 cm.
(e) After removal of the plate, dry in air and examine under ultraviolet light (254 nm).
MOBILE PHASE
12 volumes of propan-2-ol, 23 volumes of dichloromethane and 65 volumes of cyclohexane.
CONFIRMATION
The principal spot in the chromatogram obtained with solution (1) corresponds in position and size to that in the chromatogram obtained with solution (2).
B. In the Assay, the retention time of the principal peak in the chromatogram obtained with solution (1) is similar to that of the principal peak in the chromatogram obtained with solution (2).
TESTS
Related substances
Carry out the method for liquid chromatography, Appendix III D, using the following solutions prepared immediately before use in solution A.
45 volumes of a 0.14% w/v solution of potassium dihydrogen phosphate, adjusted to pH 4.0 with orthophosphoric acid, and 55 volumes of acetonitrile (solution A).
(1) Mix with the aid of ultrasound a quantity of the oral suspension containing 16 mg of Simvastatin with 30 mL of solution
A. Add a sufficient volume of solution A to produce 50 mL and mix. Centrifuge and filter (0.45-µm PVDF syringe filter is suitable).
(2) Dilute 1 volume of solution (1) to 100 volumes.
(3) 0.2% w/v of simvastatin for system suitability EPCRS.
(4) Dilute 1 volume of solution (2) to 5 volumes.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (15 cm × 2.1 mm) packed with end-capped octadecylsilyl silica gel for chromatography (3.5 µm) (Zorbax Eclipse XDB-C18 is suitable).
(b) Use gradient elution and the mobile phase described below.
(c) Use a flow rate of 0.4 mL per minute.
(d) Use a column temperature of 35°.
(e) Use a detection wavelength of 238 nm.
(f) Use an autosampler temperature of 8°
(g) Inject 5 µL of each solution.
MOBILE PHASE
Mobile phase A 40 volumes of acetonitrile and 60 volumes of a 0.1% v/v solution of orthophosphoric acid.
Mobile phase B 5 volumes of a 0.1% v/v solution of orthophosphoric acid and 95 volumes of acetonitrile.
| Time (Minutes) | Mobile phase A (% v/v) | Mobile phase B (% v/v) | Comment |
| 0-4 | 100 | 0 | isocratic |
| 4-5 | 100→80 | 0→20 | linear gradient |
| 5-33 | 80→60 | 20→40 | linear gradient |
| 33-34 | 60→0 | 40→100 | linear gradient |
| 34-37 | 0 | 100 | isocratic |
| 37-38 | 0→100 | 100→0 | linear gradient |
| 38-45 | 100 | 0 | re-equilibration |
Use the chromatogram supplied with simvastatin for system suitability EPCRS and the chromatogram obtained with solution (3) to identify the peaks due to impurities A, B C, D, E, F, G, I and J.
When the chromatograms are recorded under the prescribed conditions, the relative retentions with reference to simvastatin (retention time about 19 minutes) are: impurity I, about 0.67; impurity A, about 0.69; impurity E, about 0.81; impurity F, about 0.83; impurity G, about 0.9; impurity B, about 1.69; impurity J, about 1.74; impurity C, about 1.8 and impurity D, about 2.3.
SYSTEM SUITABILITY
The test is not valid unless in the chromatogram obtained with solution (3):
the peak-to-valley ratio is at least 1.5, where Hp is the height above the baseline of the peak due to impurity F and Hv is the height above the baseline of the lowest point of the curve separating this peak from the peak due to impurity E;
the peak-to-valley ratio is at least 1.5, where Hp is the height above the baseline of the peak due to impurity C and Hv is the height above the baseline of the lowest point of the curve separating this peak from the peak due to impurity J.
LIMITS
In the chromatogram obtained with solution (1):
the area of any peak corresponding to impurities A and I is not greater than 6 times the area of the principal peak in the chromatogram obtained with solution (2) (6%);
the area of any peak corresponding to impurity B, C, E or F is not greater than half the area of the principal peak in the chromatogram obtained with solution (2) (0.5% of each);
the area of any peak corresponding to impurity D or G is not greater than 0.4 times the area of the principal peak in the chromatogram obtained with solution (2) (0.4% of each);
the area of any other secondary peak is not greater than the area of the principal peak in the chromatogram obtained with solution (4) (0.2%);
the sum of the areas of all the secondary peaks, other than any peaks corresponding to impurities A + I, B, C, D, E, F and G, is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (1.0%).
Disregard any peak with an area less than half the area of the principal peak in the chromatogram obtained with solution (4) (0.1%).
ASSAY
45 volumes of a 0.14% w/v solution of potassium dihydrogen phosphate, adjusted to pH 4.0 with orthophosphoric acid, and 55 volumes of acetonitrile. Mix and filter (solvent B).
Carry out the method for liquid chromatography, Appendix III D protected from light, using the following solutions prepared immediately before use, in solution B.
(1) Mix with the aid of ultrasound a weighed quantity of the oral suspension containing 16 mg of Simvastatin with 30 mL of solution B. Add a sufficient volume of solution B to produce 50 mL and mix. Centrifuge and filter (0.45-µm PVDF syringe filter is suitable). Dilute 5 volumes to 200 volumes.
(2) 0.0008% w/v of simvastatin BPCRS.
(3) 0.002% w/v of each of simvastatin BPCRS and lovastatin EPCRS.
CHROMATOGRAPHIC CONDITIONS
The chromatographic conditions described under Related substances may be used. Inject 50 µL of each solution.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peaks due to simvastatin and lovastatin (impurity E) is at least 3.0.
DETERMINATION OF CONTENT
Determine the weight per mL of the oral suspension, Appendix V G, and calculate the content of C25H38O5, weight in volume, using the declared content of C25H38O5 in simvastatin BPCRS.
IMPURITIES
The impurities limited by the requirements of this monograph include those listed under Simvastatin.
