Dispersible Co-beneldopa Tablets

Dispersible Benserazide Hydrochloride and Levodopa Tablets

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

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.

93.0 to 105.0% of the stated amount.

95.0 to 105.0% of the stated amount.

A. Carry out the method for thin-layer chromatography, Appendix III A, protected from light, using a precoated cellulose plate (Merck plates are suitable) and a mixture of 10 volumes of a 10% v/v solution of hydrochloric acid, 20 volumes of water and 70 volumes of propan-2-ol as the mobile phase, but allowing the solvent front to ascend 10 cm above the line of application. Apply separately to the plate 2 µL of each of the following solutions. For solution (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. Solution (2) contains 0.5% w/v of levodopa BPCRS in 0.1m hydrochloric acid. Solution (3) contains 0.142% w/v of benserazide hydrochloride BPCRS in 0.1m hydrochloric acid. After removal of the plate, allow it to 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. 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).

Comply with the requirements for Dispersible Tablets.

A. Carry out the method for liquid chromatography, Appendix III D, using the following solutions. The solutions should be prepared in mobile phase that has been cooled to 4° and injected immediately. For solution (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. Solution (2) contains 0.0005% w/v of benserazide impurity A BPCRS in the mobile phase. Solution (3) contains 0.0005% w/v of each of benserazide hydrochloride BPCRS and benserazide impurity A BPCRS in the mobile phase.

The chromatographic procedure may be carried out using (a) a stainless steel column (12.5 cm × 4 mm) packed with octylsilyl silica gel for chromatography (5 µm) (Lichrospher RP8 is suitable), (b) as the mobile phase with a flow rate of 1.2 mL per minute a mixture prepared by dissolving 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 and (c) a detection wavelength of 220 nm.

Inject 20 µL of each solution. 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.

For solution (1) allow the chromatography to proceed for nine times the retention time of benserazide. 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 principal peak in the chromatogram obtained with solution (2) (0.5%), the area of any other secondary peak is not greater than the area of the peak due to benserazide in the chromatogram obtained with solution (3) (0.5%) and the sum of the areas of any such peaks is not greater than twice the area of the peak due to benserazide in the chromatogram obtained with solution (3) (1%). Disregard any peak with an area less than 0.1 times the area of the peak due to benserazide in the chromatogram obtained with solution (3) (0.05%).

B. Carry out the method for thin-layer chromatography, Appendix III A, using a precoated cellulose plate (Merck plates are suitable) and a mixture of 10 volumes of a 10% v/v solution of hydrochloric acid, 20 volumes of water and 70 volumes of propan-2-ol as the mobile phase. 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. Solution (1) should be prepared immediately before use. For solution (1) shake a quantity of the powdered tablets containing 0.1 g of Levodopa with 10 mL of a mixture of equal volumes of anhydrous formic acid and methanol, filter and use the filtrate. For solution (2) dilute 1 volume of solution (1) to 200 volumes with methanol. Solution (3) is a mixture of 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. After removal of the plate, allow it to 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. 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%). 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).

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

The chromatographic procedure may be carried out using (a) a stainless steel column (25 cm × 4 mm) packed with octylsilyl silica gel for chromatography (5 µm) (Lichrospher RP8 is suitable), (b) as the mobile phase with a flow rate of 1.2 mL per minute a mixture prepared by dissolving 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 and (c) a detection wavelength of 220 nm. Inject 20 µL of each solution.

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.

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.

Dispersible Co-beneldopa Tablets should be protected from moisture.

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