Divalproex Sodium Extended-Release Tablets
DEFINITION
Divalproex Sodium Extended-Release Tablets contain an amount of divalproex sodium equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of valproic acid (C8H16O2).
IDENTIFICATION
• The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.
ASSAY
• Procedure
Buffer:
0.5 g of citric acid monohydrate and 0.4 g of dibasic sodium phosphate in 1 L of water
Diluent:
Buffer adjusted with phosphoric acid to a pH of 2.0
Standard stock solution:
2.5 mg/mL of USP Valproic Acid RS in methanol
Standard solution:
1.0 mg/mL of USP Valproic Acid RS from the Standard stock solution and Diluent
Sample stock solution:
Transfer an amount of powder (from NLT 20 Tablets) to a suitable volumetric flask to obtain a nominal concentration of 2.5 mg/mL of valproic acid. Dissolve in 50% of the flask volume of methanol by shaking for 1 h. Dilute with methanol to volume and pass through a suitable filter.
Sample solution:
1.0 mg/mL of valproic acid from the filtrate of the Sample stock solution in Diluent
Mobile phase:
Methanol and Buffer (11:9). Adjust with phosphoric acid to a pH of 5.0.
Chromatographic system
Mode:
LC
Detector:
UV 210 nm
Column:
3.9-mm × 15-cm; 4-µm packing L11
Flow rate:
0.7 mL/min
Injection size:
20 µL
System suitability
Sample:
Standard solution
Suitability requirements
Tailing factor:
NMT 2.0 for valproic acid
Relative standard deviation:
NMT 2.0% for valproic acid
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of valproic acid (C8H16O2) in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response from the Sample solution |
| rS | = | = peak response from the Standard solution |
| CS | = | = concentration of USP Valproic Acid RS in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of valproic acid in the Sample solution (mg/mL) |
Acceptance criteria:
90.0%–110.0% of valproic acid
PERFORMANCE TESTS
• Dissolution 
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711
Test 1
Acid stage medium:
0.1 N of hydrochloric acid; 500 mL
Buffer stage medium:
21.6 g of sodium dodecyl sulfate, 6.9 g of sodium dihydrogen phosphate monohydrate, and 0.12 g of sodium hydroxide in 1 L of water. Adjust with diluted sodium hydroxide or phosphoric acid to a pH of 5.5; 900 mL.
Apparatus 2:
100 rpm, with three prong sinkers only for 250 mg Tablets
Times:
45 min in the Acid stage medium; 3, 12, and 24 h in the Buffer stage medium
Analysis:
After 45 min in the Acid stage medium, withdraw a sample from the solution, and immediately filter. Replace the Acid stage medium with the Buffer stage medium and run the test for the times specified.
Standard stock solution:
2.5 mg/mL of USP Valproic Acid RS in methanol
Standard solution:
0.15 mg/mL of USP Valproic Acid RS from the Standard stock solution in the Buffer stage medium.[Note—Add 40% of the flask volume of methanol before diluting with Buffer stage medium to volume. ]
Buffer:
1.42 g of sodium phosphate dibasic and 0.5 mL of glacial acetic acid in 1 L of water. Adjust with phosphoric acid to a pH of 2.5.
Sample solution:
Pass a portion of the solution under test through a suitable 20-µm filter. Use the Sample solution from the Acid stage medium as is. Dilute the Sample solution from the Buffer stage medium with methanol by a factor of 2.
Mobile phase:
Methanol and Buffer (13:7)
Chromatographic system
Mode:
LC
Detector:
UV 210 nm
Column:
3.9-mm × 15-cm; 10-µm packing L11
Column temperature:
30
Flow rate:
1 mL/min
Injection size:
80 µL
Run time:
6 min
System suitability
Sample:
Standard solution
Suitability requirements
Tailing factor:
NMT 2.5
Relative standard deviation:
NMT 2.0%
Analysis
Samples:
Sample solutions from the Acid stage medium, Buffer stage medium, and Standard solution
Calculate the percentage of valproic acid dissolved in the Acid stage medium:
Result = (rU/rS) × (CS/L) × VA × 100
| rU | = | = peak response from the Sample solution |
| rS | = | = peak response from the Standard solution |
| CS | = | = concentration of USP Valproic Acid RS in the Standard solution (mg/mL) |
| L | = | = label claim (mg/Tablet) |
| VA | = | = volume of Acid stage medium, 500 mL |
Calculate the concentration of valproic acid dissolved in the Buffer stage medium at the time interval, t, in mg/mL:
Ct = (rU/rS) × (CS × DU) × 2
| rU | = | = peak response from the Sample solution |
| rS | = | = peak response from the Standard solution |
| CS | = | = concentration of USP Valproic Acid RS in the Standard solution (mg/mL) |
| DU | = | = dilution factor of the Sample solution in the Buffer stage medium, 2 |
Calculate the percentage of valproic acid in the Buffer stage medium at the first time interval:
Result = C1 × VB × 100/L
| C1 | = | = concentration of valproic acid in the Buffer stage medium at the first time interval (mg/mL) |
| VB | = | = volume of Buffer stage medium, 900 mL |
| L | = | = label claim (mg/Tablet) |
Calculate the percentage of valproic acid dissolved in the Buffer stage medium at the second time interval:
Result = [C2 × (VB 
VS)] + (C1 × VS) × 100/L
VS)] + (C1 × VS) × 100/L| C2 | = | = concentration of valproic acid in the Buffer stage medium at the second time interval (mg/mL) |
| VB | = | = volume of Buffer stage medium, 900 mL |
| VS | = | = volume of sample taken at each time interval (mL) |
| C1 | = | = concentration of valproic acid in the Buffer stage medium at the first time interval (mg/mL) |
| L | = | = label claim (mg/Tablet) |
Calcluate the percentage of valproic acid dissolved in the Buffer stage medium at the nth time interval:
Result = Cn × (VB (n-1) × VS) + [(C1 + C2 + ....+ Cn-1) × VS] × 100/L
(n-1) × VS) + [(C1 + C2 + ....+ Cn-1) × VS] × 100/L| Cn | = | = concentration of valproic acid in the Buffer stage medium at the nth time interval (mg/mL) |
| VB | = | = volume of Buffer stage medium, 900 mL |
| VS | = | = volume of sample taken (mL) |
| C1 | = | = concentration of valproic acid dissolved in the first time interval in the Buffer stage medium (mg/mL) |
| C2 | = | = concentration of valproic acid dissolved in the second time interval in the Buffer stage medium (mg/mL) |
| Cn-1 | = | = concentration of valproic acid dissolved in the (n-1)th time interval in the Buffer stage medium (mg/mL) |
| L | = | = label claim (mg/Tablet) |
Tolerances
Acid stage:
NLT 10% of the labeled amount of valproic acid is dissolved.
Buffer stage:
The percentage of the labeled amount of valproic acid dissolved at the times specified conform to Acceptance Table 2.
| Time (h) |
Amount Dissolved (Tablets labeled to contain 500 mg of valproic acid) |
Amount Dissolved (Tablets labeled to contain 250 mg of valproic acid) |
|---|---|---|
| 3 | 10%–30% | 10%–30% |
| 9 | 35%–55% | 35%–60% |
| 12 | 45%–70% | 45%–75% |
| 24 | NLT 75% | NLT 75% |
Test 2:
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.
Acid stage medium:
0.1 N of hydrochloric acid; 500 mL
Buffer stage concentrate:
15.53 g/L of sodium phosphate monobasic monohydrate, 5.45 g/L of sodium hydroxide, and 48.65 g of sodium lauryl sulfate/L in water, final pH approximately 11); 400 mL
Buffer stage medium:
Mix 400 mL of Buffer stage concentrate with 500 mL of Acid stage medium to a pH of 5.5 ± 0.05. If necessary, adjust the pH of the Buffer stage medium with 1 N of hydrochloric acid or 1 N of sodium hydroxide to assure that the final pH of the mixture of media is 5.5. Retain this solution to dilute the solutions prepared later.
Apparatus 2:
100 rpm, with wire helix sinkers
Times:
45 min in the Acid stage medium; 3, 9, 12, and 21 h in the Buffer stage medium
Procedure:
After 45 min in Acid stage medium, stop and lift the paddles from the vessels. Do not perform an analysis of the Acid stage medium. Transfer 400 mL of pH adjusted Buffer stage medium to the vessels containing the Acid stage medium and run the test for the times specified.
Standard stock solution:
28 mg/mL of USP Valproic Acid RS in a suitable volumetric flask, dissolve with 20% of the flask volume of 1 N of sodium hydroxide, and dilute with water to volume. Dilute this solution with Buffer stage medium to obtain a final concentration of about 2.8 mg/mL.
Standard solutions:
Prepare a series of dilutions in Buffer stage medium from the Standard stock solution in the concentrations of 0.028 mg/mL, 0.11 mg/mL, 0.22 mg/mL, 0.50 mg/mL, and 0.70 mg/mL.
Sample solution:
Withdraw 10 mL of the solution under test and pass through a suitable 35-µm filter.
Buffer:
3.5 g/L of sodium phosphate monobasic monohydrate in water. Adjust with phosphoric acid to a pH of 3.5.
Mobile phase:
Acetonitrile and Buffer (1:1)
Chromatographic system
Mode:
LC
Detector:
UV 215 nm
Column:
4.6-mm × 15-cm; 5-µm packing L7
Flow rate:
1 mL/min
Injection size:
50 µL
System suitability
Samples:
0.028, 0.11, 0.22, 0.50, and 0.70 mg/mL of the Standard solutions
Suitability requirements
Tailing factor:
NMT 2.0, using the 0.50 mg/mL of Standard solution
Relative standard deviation:
NMT 2.0%
Correlation coefficient:
NLT 0.999, using the five concentrations of the Standard solution
Analysis
Samples:
Sample solutions
From the standard curve, determine the amount of valproic acid dissolved at each time interval using the response of each Sample solution. Calculate the percentage of valproic acid dissolved in the Buffer stage medium at the first time interval:
Result = (C1 × VB) × 100/L
| C1 | = | = concentration of valproic acid in the Buffer stage medium at the 3 h time interval (mg/mL) |
| VB | = | = volume of Buffer stage medium, 900 mL |
| L | = | = label claim (mg/Tablet) |
Calculate the percentage of valproic acid dissolved in the Buffer stage medium at the nth time interval:
Result = Cn × (VB (n-1) × VS) + [(C1 + C2 + ....+ Cn-1) × VB] × 100/L
(n-1) × VS) + [(C1 + C2 + ....+ Cn-1) × VB] × 100/L| Cn | = | = concentration of valproic acid in the Buffer stage medium at the nth time interval (mg/mL) |
| VB | = | = volume of Buffer stage medium, 900 mL |
| VS | = | = volume of sample taken (mL) |
| C1 | = | = concentration of valproic acid dissolved in the first time interval in the Buffer stage medium (mg/mL) |
| C2 | = | = concentration of valproic acid dissolved in the second time interval in the Buffer stage medium (mg/mL) |
| Cn-1 | = | = concentration of valproic acid dissolved in the (n-1)th time interval in the Buffer stage medium (mg/mL) |
| L | = | = label claim (mg/Tablet) |
Tolerances:
The percentage of the labeled amount of valproic acid dissolved at the times specified conform to the following acceptance table:
| 3 h | 9 h | 12 h | 21 h | ||
|---|---|---|---|---|---|
| L1 | Individual Tablets | 10%–27% | 35%–70% | 44%–92% | NLT 87% |
| L2 | Average | 10%–27% | 35%–70% | 44%–92% | NLT 87% |
| L2 | Individual Tablets | 0–37% | 25%–80% | 34%–102% | NLT 77% |
| L3 | Average | 10%–27% | 35%–70% | 44%–92% | NLT 87% |
| L3 | Individual Tablets | NMT 2 Tablets are outside the range of 0%–37% and no individual Tablet is outside the range of 0%–47% | NMT 2 Tablets are outside the range of 25%–80% and no individual Tablet is outside the range of 15%–90% | NMT 2 Tablets are outside the range of 34%–102% and no individual Tablet is outside the range of 24%–112% | NMT 2 Tablets release less than 77% and no individual Tablet releases less than 67% |
• Uniformity of Dosage Units 905:
Meet the requirements
905:
Meet the requirements
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in well-closed containers at controlled room temperature.
• Labeling:
When more than one Dissolution test is given, the labeling states the Dissolution test used only if Test 1 is not used.
• USP Reference Standards 11
11
USP Valproic Acid RS 
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Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Ravi Ravichandran, Ph.D.
Principal Scientific Liaison 1-301-816-8330 |
(SM42010) Monographs - Small Molecules 4 |
| 711 |
Margareth R.C. Marques, Ph.D.
Senior Scientific Liaison 1-301-816-8106 |
(GCDF2010) General Chapters - Dosage Forms |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 2948
Pharmacopeial Forum: Volume No. 36(2) Page 391