Gastro-resistant Sodium Valproate Tablets
Sodium Valproate Gastro-resistant Tablets from different manufacturers, whilst complying with the requirements of the monograph, may not be interchangeable.
Action and use
Antiepileptic.
DEFINITION
Sodium Valproate Gastro-resistant Tablets contain Sodium Valproate. They are made gastro-resistant by enteric-coating or by other means.
The tablets comply with the requirements stated under Tablets and with the following requirements.
Content of sodium valproate, C8H15NaO2
95.0 to 105.0% of the stated amount.
IDENTIFICATION
A. Shake a quantity of the powdered tablets containing 0.5 g of Sodium Valproate with 10 mL of water and centrifuge. Acidify 5 mL of the supernatant liquid with 2M sulfuric acid, shake with 25 mL of dichloromethane and wash the dichloromethane layer with 5 mL of water. Dry by shaking with anhydrous sodium sulfate, filter and evaporate the dichloromethane to dryness. The infrared absorption spectrum of a thin film of the residue, Appendix II A, is concordant with the reference spectrum of valproic acid (RS 431).
B. Shake a quantity of the powdered tablets containing 0.25 g of Sodium Valproate with 3 mL of water and centrifuge. To 2 mL of the supernatant liquid add 0.5 mL of a 10% w/v solution of cobalt(II) nitrate. A purple precipitate is produced which is soluble in dichloromethane.
TESTS
Dissolution
Comply with the dissolution test for tablets and capsules, Appendix XII B1.
TEST CONDITIONS
First stage
(a) Use Apparatus 1, rotating the basket at 100 revolutions per minute.
(b) Use 900 mL of 0.1M hydrochloric acid, at a temperature of 37°, as the medium.
PROCEDURE
(1) After 2 hours, withdraw a sample of the medium and filter.
(2) 0.001% w/v of sodium valproate BPCRS in 0.1M hydrochloric acid.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (30 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 μm) (μBondapak C18 is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 2 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 220 nm.
(f) Inject 50 μL of each solution.
MOBILE PHASE
45 volumes of a 0.32% w/v solution of potassium dihydrogen orthophosphate adjusted to pH 3.0 with orthophosphoric acid and 55 volumes of acetonitrile.
DETERMINATION OF CONTENT
Calculate the total content of sodium valproate, C8H15NaO2, in the medium using the declared content of C8H15NaO2 in sodium valproate BPCRS.
LIMITS
The amount of sodium valproate released is not more than 5% of the stated amount.
Final stage
(a) Use Apparatus 1, rotating the basket at 100 revolutions per minute.
(b) Replace the 0.1M hydrochloric acid in the vessel with 900 mL of phosphate buffer pH 6.8, previously held at 37°, as the medium.
PROCEDURE
(1) After 60 minutes, withdraw a sample of the medium and filter. Use the filtrate diluted, if necessary, to give a solution expected to contain 0.002% w/v of Sodium Valproate.
(2) 0.002% w/v solution of sodium valproate BPCRS in the dissolution medium.
CHROMATOGRAPHIC CONDITIONS
The chromatographic conditions described under the first stage may be used.
DETERMINATION OF CONTENT
Calculate the total content of sodium valproate, C8H15NaO2, in the medium using the declared content of C8H15NaO2 in sodium valproate BPCRS.
LIMITS
The amount of sodium valproate released after the final stage is not less than 65% (Q) of the stated amount.
Related substances
Carry out the method for gas chromatography, Appendix III B, using the following solutions.
(1) 0.005% w/v of octanoic acid in dichloromethane (internal standard solution).
(2) Disperse a quantity of the powdered tablets containing 1 g of Sodium Valproate with 20 mL of 0.1M sodium hydroxide, and mix with the aid of ultrasound for 30 minutes. Centrifuge the solution and transfer 10 mL of the supernatant into a separating funnel. Mix the resulting solution with 1 mL of 2M sulfuric acid and add 10 mL of solution (1). Extract the mixture with three 20-mL quantities of dichloromethane and combine the organic layers. Dry by shaking with anhydrous sodium sulfate, and filter (a GF/A filter is suitable). Reduce the volume of the filtrate at a temperature not exceeding 30° and dilute to 10 mL with dichloromethane.
(3) Dilute 1 volume of solution (2) to 100 volumes with solution (1). Dilute 1 volume of the resulting solution to 10 volumes with solution 1.
(4) 5% w/v of valproic acid for system suitability EPCRS in dichloromethane.
CHROMATOGRAPHIC CONDITIONS
(a) Use a fused silica capillary column (30 m × 0.53 mm) bonded with a 0.5-μm layer of macrogol 20,000 2- nitroterephthalate (DB-FFAP is suitable).
(b) Use helium as the carrier gas at 8 mL per minute.
(c) Use the temperature gradient conditions as described below.
(d) Use an injection temperature of 220°.
(e) Use a flame ionisation detector at 220°.
(f) Inject 1 μL of each solution.
(g) Use a split ratio of 1:10.
| Time (Minutes) | Temperature (°C) | Comment |
| 0-5 | 80 | isothermal |
| 5-15 | 80→150 | linear gradient |
| 15-28.3 | 150→190 | linear gradient |
| 28.3-30 | 190 | isothermal |
| 30-35 | 190→250 | linear gradient |
| 35-45 | 250 | isothermal |
When the chromatograms are recorded under the prescribed conditions, the relative retentions with reference to valproic acid (retention time, about 15 minutes) are: impurity K, about 0.97; octanoic acid, about 1.12.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (4), the resolution between the peaks due to impurity K and valproic acid is at least 2.0.
LIMITS
Using the chromatogram obtained with solution (3), calculate the ratio of the area of the peak due to valproic acid to the area of the peak due to the internal standard (R).
In the chromatogram obtained with solution (2):
the ratio of the area of the peak due to impurity K to the area of the peak due to the internal standard is not greater than 2R (0.2%);
the ratio of the area of any secondary peak to the area of the peak due to the internal standard is not greater than R (0.1%);
the ratio of the sum of the areas of any secondary peaks to the area of the peak due to the internal standard is not greater than 4R (0.4%).
Disregard any peak where the ratio of the area of any peak to the area of the peak due to the internal standard is not greater than half of R (0.05%) and any peak eluting after 30 minutes.
ASSAY
Weigh and powder 20 tablets. Carry out the method for liquid chromatography, Appendix III D using the following solutions.
Solution A: Dissolve 6.8 g of potassium dihydrogen orthophosphate in 1000 mL of water and adjust to pH 6.8 with 0.2M sodium hydroxide.
(1) Shake and mix with the aid of ultrasound a quantity of the powdered tablets containing 0.5 g of Sodium Valproate with 50 mL of acetonitrile R1. Add 100 mL of solution A and mix further with the aid of ultrasound. Dilute the solution to 200 mL and filter (a 0.2-μm nylon filter is suitable). Dilute 1 volume of this solution to 5 volumes with solution A.
(2) Mix with the aid of ultrasound 50 mg of sodium valproate BPCRS with 5 mL of acetonitrile R1. Add 10 mL of solution A and mix further with the aid of ultrasound. Dilute the resulting solution to 100 mL with solution A.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (25 cm × 4.6 mm) packed with base-deactivated end-capped octadecylsilyl silica gel for chromatography (5 μm) (Hypersil BDS C18 is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1.0 mL per minute.
(d) Use a column temperature of 25°.
(e) Use a detection wavelength of 210 nm.
(f) Inject 20 μL of each solution.
MOBILE PHASE
50 volumes of acetonitrile R1 and 50 volumes of a solution prepared by dissolving 1.56 g of sodium dihydrogen orthophosphate in 1000 mL of water and adjusting the pH to 2.3 with orthophosphoric acid.
DETERMINATION OF CONTENT
Calculate the content of C8H15NaO2 in the tablets using the declared content of C8H15NaO2 in sodium valproate BPCRS.
IMPURITIES
The impurities limited by the requirements of this monograph include those listed under Sodium Valproate.
