Divalproex Sodium Delayed-Release Capsules
DEFINITION
Divalproex Sodium Delayed-Release Capsules contain an amount of divalproex sodium equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of valproic acid (C8H16O2).
IDENTIFICATION
• A. Infrared Absorption 
197K
197K
Diluent:
Acetonitrile and water (1:1)
Standard:
Prepare as directed in 197F using USP Valproic acid RS.
197F using USP Valproic acid RS.
Sample:
Dissolve the contents of 20 Capsules and 30 mL of Diluent in a 50-mL volumetric flask. Sonicate to dissolve for 30 min. Dilute with Diluent to volume. Centrifuge the solution at 3000 rpm for about 20 min. Pipet 20 mL of the supernatant into a separatory funnel. Extract with 50 mL of n-hexane. Collect the n-hexane layer, and evaporate the solvent. Cast 1 mg of the liquid obtained after evaporation to NaCl windows.
• B.
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:
6.8 g/L of monobasic potassium phosphate, adjusted with phosphoric acid to a pH of 3.0
Diluent:
Acetonitrile and water (1:1)
Standard solution:
Transfer a suitable amount of USP Valproic Acid RS to a suitable volumetric flask to obtain a solution having a final concentration of 2.5 mg/mL of valproic acid. Add 40% of the flask volume of Diluent. Sonicate for 5 min, and add 20% of the flask volume of 0.1 N hydrochloric acid. Dilute with Diluent to volume.
Sample solution:
Transfer an amount of contents (from NLT 20 Capsules) to a suitable volumetric flask to obtain a nominal concentration of 2.5 mg/mL of valproic acid. Dissolve in 20% of the flask volume of 0.1 N hydrochloric acid, and sonicate for 5 min. Add 60% of the flask volume of Diluent, and sonicate for an additional 25 min. Dilute with Diluent to volume. Centrifuge at 4000 rpm for 10 min, and use the clear supernatant.
Mobile phase:
Acetonitrile and Buffer (2:3)
Chromatographic system
Mode:
LC
Detector:
UV 215 nm
Column:
4.6-mm × 15-cm; 5-µm packing L1
Flow rate:
1.8 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 Capsules 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 711
711
Medium:
Phosphate buffer, pH 7.5 (6.8 g/L of monobasic potassium phosphate and 1.64 g/L of sodium hydroxide in water, adjusted with 0.08 N hydrochloric acid to a pH of 7.5); 500 mL, degassed
Apparatus 2:
50 rpm, with sinkers
Time:
2, 4, and 6 h
Buffer and Mobile phase:
Prepare as directed in the Assay.
Standard stock solution:
1.6 mg/mL of USP Valproic Acid RS in Mobile phase
Standard solution:
0.26 mg/mL of valproic acid from Standard stock solution and Medium
Sample solution:
Pass a portion of the solution under test through a suitable 0.45-µm filter. Replace the volume withdrawn with an equal volume of Medium previously heated at 37.0 ± 0.5
.
.
Chromatographic system
Mode:
LC
Detector:
UV 210 nm
Column:
4.6-mm × 15-cm; 5-µm packing L1
Flow rate:
1.8 mL/min
Injection size:
40 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 dissolved (Di) at each time interval:
Di = (rU/rS) × (CS/L) × V × 100
| rU | = | = peak response from the Sample solution |
| rS | = | = peak response from the Standard solution |
| CS | = | = concentration of the Standard solution (mg/mL) |
| L | = | = label claim (mg/Capsule) |
| V | = | = volume of Medium, 500 mL |
percentage of valproic acid dissolved at 2 h = D1
percentage of valproic acid dissolved at 4 h = D2 + [(D1/V) × VS]
percentage of valproic acid dissolved at 6 h = D3 + [(D1/V) × VS] + [(D2/V) × VS]
| V | = | = volume of Medium, 500 mL |
| VS | = | = volume withdrawn at each sampling time (mL) |
Tolerances:
NLT 20% of the labeled amount of valproic acid is dissolved in 2 h; NLT 70% of the labeled amount of valproic acid is dissolved in 4 h; and NLT 85% of the labeled amount of valproic acid is dissolved in 6 h.
• Uniformity of Dosage Units 905:
Meet the requirements
905:
Meet the requirements
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in tight, light-resistant containers at controlled room temperature.
• Labeling:
Divalproex Delayed Release Capsules may be swallowed whole or may be administered by carefully opening the Capsule and sprinking the entire contents on a small amount of soft food. This drug/food mixture should be swallowed immediately and not chewed. It should not be stored for future use.
• 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 2946
Pharmacopeial Forum: Volume No. 36(2) Page 390