Etoposide Capsules

General Notices

Action and use

Inhibitor of DNA topoisomerase type II; cytotoxic.

Definition

Etoposide Capsules contain a solution of Etoposide in a suitable water-miscible vehicle.

The capsules comply with the requirements stated under Capsules and with the following requirements.

Content of etoposide, C₂₉H₃₂O₁₃

95.0 to 105.0% of the stated amount.

Identification

Add a quantity of the contents of the capsules containing 0.1 g of Etoposide to a separating funnel containing 100 mL of water, extract with two 20 mL quantities of dichloromethane, dry the combined organic extracts over anhydrous sodium sulfate and filter. Extract the filtrate with 30 mL of water, filter the dichloromethane layer through anhydrous sodium sulfate and evaporate to dryness at 25° to 35° under reduced pressure. Dissolve the oily residue in 5 mL of water, shake gently and allow to stand for 30 minutes. Filter through a sintered-glass funnel, wash the precipitate in the funnel with three 20 mL quantities of water and dry the precipitate in the funnel at 40° at a pressure of 2 kPa for 90 minutes. The infrared absorption spectrum of the dried precipitate, Appendix II A, is concordant with the reference spectrum of etoposide (RS 396).

Tests

Dissolution

Comply with the requirements for Monographs of the British Pharmacopoeia in the dissolution test for tablets and capsules, Appendix XII B1, using Apparatus 2. Use as the medium 900 mL of a pH 4.5 buffer prepared by dissolving 2.99 g of sodium acetate and 14 mL of 2m acetic acid in sufficient water to produce 1000 mL and rotate the paddle at 50 revolutions per minute. Withdraw a sample of 10 mL of the medium and filter. Carry out the method for liquid chromatography, Appendix III D, using the following solutions. For solution (1) use the filtrate diluted, if necessary, with dissolution medium to produce a solution expected to contain about 0.005% w/v of Etoposide. Solution (2) contains 0.005% w/v of etoposide BPCRS in the dissolution medium. Solution (3) contains 0.005% w/v of etoposide BPCRS and 0.00025% w/v of ethyl parahydroxybenzoate in the dissolution medium.

The chromatographic procedure may be carried out using (a) a stainless steel column (30 cm × 3.9 mm) packed with phenyl silica gel for chromatography (10 µm) (µBondapak phenyl is suitable), (b) as the mobile phase with a flow rate of 1.0 mL per minute a mixture of 26 volumes of acetonitrile and 74 volumes of a 0.272% w/v solution of sodium acetate adjusted to pH 4.0 with glacial acetic acid and (c) a detection wavelength of 254 nm.

The test is not valid unless, in the chromatogram obtained with solution (3), the resolution factor between the two principal peaks is at least 2.0.

Calculate the total content of etoposide, C₂₉H₃₂O₁₃, in the medium using the declared content of C₂₉H₃₂O₁₃ in etoposide BPCRS.

cis-Etoposide

Carry out the method for liquid chromatography, Appendix III D, using the following solutions. For solution (1) add 80 mL of the mobile phase to 10 whole capsules and stir mechanically for 15 minutes with occasional shaking. Add sufficient mobile phase to produce 100 mL and stir for a further 5 minutes. Dilute, if necessary, a volume of the solution with the mobile phase to give a solution containing 0.5% w/v of Etoposide; use immediately. For solution (2) dilute 1 volume of solution (1) to 50 volumes with the mobile phase. For solution (3) prepare a 0.5% w/v solution of etoposide BPCRS in a mixture of 50 volumes of acetonitrile, 50 volumes of water and 0.1 volume of triethylamine and allow to stand for 40 minutes.

The chromatographic procedure described under Dissolution may be used.

The test is not valid unless, in the chromatogram obtained with solution (3), the resolution factor between the principal peak and the peak immediately following the principal peak (cis-etoposide) is at least 1.0.

In the chromatogram obtained with solution (1) the area of any peak corresponding to cis-etoposide is not greater than the area of the peak in the chromatogram obtained with solution (2) (2%).

Assay

Carry out the method for liquid chromatography, Appendix III D, using the following solutions. For solution (1) add 400 mL of the mobile phase to 10 whole capsules and stir mechanically for 15 minutes with occasional shaking. Add sufficient mobile phase to produce 500 mL and stir for a further 5 minutes. Dilute a volume of the solution with the mobile phase to give a solution containing 0.04% w/v of Etoposide. Solution (2) contains 0.04% w/v of etoposide BPCRS in the mobile phase. Solution (3) contains 0.005% w/v of etoposide BPCRS and 0.00025% w/v of ethyl parahydroxybenzoate in the mobile phase.