Dispersible Co-beneldopa Tablets

General Notices

Dispersible Benserazide Hydrochloride and Levodopa Tablets

Action and use

Dopa decarboxylase inhibitor + dopamine precursor; treatment of Parkinson’s disease.

Definition

Dispersible Co-beneldopa Tablets contain Benserazide Hydrochloride and Levodopa in the proportions, by weight, 1 part benserazide to 4 parts levodopa in a suitable dispersible basis.

The tablets comply with the requirements stated under Tablets and with the following requirements.

Content of benserazide, C10H15N3O5

93.0 to 105.0% of the stated amount.

Content of levodopa, C9H11NO4

95.0 to 105.0% of the stated amount.

Identification

Carry out the method for thin-layer chromatography, Appendix III A, using the following solutions. Carry out the test protected from light and prepare the solutions immediately before use.
(1) Shake a quantity of the powdered tablets containing 0.2 g of Levodopa with 40 mL of 0.1m hydrochloric acid for 10 minutes, filter and use the filtrate.
(2) 0.5% w/v of levodopa BPCRS in 0.1m hydrochloric acid.
(3) 0.142% w/v of benserazide hydrochloride BPCRS in 0.1m hydrochloric acid.
chromatographic conditions
(a) Use a precoated cellulose plate (Merck plates are suitable).
(b) Use mobile phase described below.
(c) Apply 2 µL of each solution.
(d) Develop the plate to 10 cm.
(e) After removal of the plate, dry in a current of warm air for 5 minutes, spray with dilute phosphomolybdotungstic reagent, dry in a current of warm air for 30 seconds and spray with a 10% w/v solution of sodium hydroxide.
mobile phase

10 volumes of a 10% v/v solution of hydrochloric acid, 20 volumes of water and 70 volumes of propan-2-ol.

confirmation

The chromatogram obtained with solution (1) shows two clearly separated spots, the spot with the higher Rf value corresponding to the spot in the chromatogram obtained with solution (2) and the spot with the lower Rf value corresponding to the spot in the chromatogram obtained with solution (3).

B. In the Assay, the chromatogram obtained with solution (1) exhibits two peaks with the same retention times as those due to benserazide and levodopa in the chromatogram obtained with solution (2).

Tests

Related substances

A. Carry out the method for liquid chromatography, Appendix III D, using the following solutions. Use freshly prepared solutions. Store and inject the solutions at 4°, using a cooled autosampler.
(1) Shake a quantity of the powdered tablets containing the equivalent of 0.1 g of benserazide with 100 mL of the mobile phase, mix with the aid of ultrasound for 3 minutes, shaking occasionally, and filter through a 0.45-µm filter, discarding the first 5 mL of filtrate.
(2) 0.0005% w/v of each of benserazide hydrochloride BPCRS, benserazide impurity A BPCRS and benserazide impurity B BPCRS in the mobile phase.
chromatographic conditions
(a) Use a stainless steel column (12.5 cm × 4.0 mm) packed with octylsilyl silica gel for chromatography (5 µm) (Lichrospher 100 RP8 is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1.2 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 220 nm.
(f) Inject 20 µL of each solution.
(g) For solution (1) allow the chromatography to proceed for nine times the retention time of benserazide.
mobile phase

Dissolve 4.76 g of potassium dihydrogen orthophosphate in 800 mL of water, adding 200 mL of acetonitrile and 1.22 g of sodium decanesulfonate and adjusting the pH to 3.5 with orthophosphoric acid.

When the chromatograms are recorded under the prescribed conditions, the relative retentions with reference to benserazide (retention time about 7 minutes) are: levodopa, about 0.3; benserazide impurity A, about 0.7; benserazide impurity B, about 3.2.

system suitability

The test is not valid unless, in the chromatogram obtained with solution (2), the resolution between the peaks due to benserazide and impurity A is at least 2.0.

limits

In the chromatogram obtained with solution (1):

the area of any peak corresponding to benserazide impurity A is not greater than the area of the corresponding peak in the chromatogram obtained with solution (2) (0.5%);

the area of any peak corresponding to benserazide impurity B is not greater than twice the area of the principal peak in the chromatogram obtained with solution (2) (1.0%);

the area of any other secondary peak is not greater than 0.4 times the area of the peak due to benserazide in the chromatogram obtained with solution (2) (0.2%);

the sum of the areas of any secondary peaks is not greater than 4 times the area of the peak due to benserazide in the chromatogram obtained with solution (2) (2.0%).

Disregard any peak with an area less than 0.2 times the area of the peak due to benserazide in the chromatogram obtained with solution (2) (0.1%).
B. Carry out the method for thin-layer chromatography, Appendix III A, using the following solutions.
(1) Prepare immediately before use; shake a quantity of the contents of the capsules containing 0.1 g of Levodopa with 10 mL of a mixture of equal volumes of anhydrous formic acid and methanol.
(2) Dilute 1 volume of solution (1) to 200 volumes with methanol.
(3) Equal volumes of solution (1) and a solution prepared by dissolving 30 mg of l-tyrosine in 1 mL of anhydrous formic acid and diluting to 100 mL with methanol.
chromatographic conditions
(a) Use a precoated cellulose plate (Merck plates are suitable).
(b) Use the mobile phase as described below.
(c) Apply separately to the plate, as bands 20 mm long, 10 µL of each of solutions (1) and (2) and 20 µL of solution (3) and dry in a current of air.
(d) Develop the plate to 15 cm.
(e) After removal of the plate, dry in a current of warm air, spray with a freshly prepared mixture containing equal volumes of a 10% w/v solution of iron(iii) chloride hexahydrate and a 5% w/v solution of potassium hexacyanoferrate(iii) and examine the plate immediately.
mobile phase

10 volumes of a 10% v/v solution of hydrochloric acid, 20 volumes of water and 70 volumes of propan-2-ol.

system suitability

The test is not valid unless the chromatogram obtained with solution (3) shows a distinct band, at a higher Rf value than the principal band, which is more intense than the band in the chromatogram obtained with solution (2).

limits

Any secondary band in the chromatogram obtained with solution (1) is not more intense than the band in the chromatogram obtained with solution (2) (0.5%).

Assay

Weigh and powder 20 tablets. Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1) Shake a quantity of the powdered tablets containing 0.1 g of Levodopa with 80 mL of 0.1m orthophosphoric acid for 5 minutes, mix with the aid of ultrasound for 30 minutes, cool, add sufficient 0.1m orthophosphoric acid to produce 100 mL and mix. Filter the resulting solution through a 0.45-µm filter (Whatman GF/C is suitable), discarding the first 5 mL of filtrate, and dilute 10 volumes of the filtrate to 100 volumes with the mobile phase.
(2) Dissolve 28.7 mg of benserazide hydrochloride BPCRS and 0.1 g of levodopa BPCRS in sufficient 0.1m orthophosphoric acid to produce 100 mL, mix and dilute 10 volumes of the resulting solution to 100 volumes with the mobile phase.
chromatographic conditions

The chromatographic conditions described under Related substances may be used. Use a detection wavelength of 220 nm for benserazide and 270 nm for levodopa.

system suitability

The chromatogram obtained with solution (2) shows two principal peaks; the retention time of the peak due to benserazide is about three times that of the peak due to levodopa.

determination of content

Calculate the content of C10H15N3O5 and of C9H11NO4 in each tablet using the declared contents of C10H15N3O5 in benserazide hydrochloride BPCRS and of C9H11NO4 in levodopa BPCRS.

Storage

Dispersible Co-beneldopa Tablets should be protected from moisture.

Labelling

The quantity of Benserazide Hydrochloride is stated in terms of the equivalent amount of benserazide.

Impurities

The impurities limited by the requirements of this monograph include impurities A and B listed under Benserazide Hydrochloride.