Divalproex Sodium Delayed-Release Capsules

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition
Issued and maintained by the United States Pharmacopeial Convention (USP)
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1 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).

2 IDENTIFICATION

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K

Diluent: Acetonitrile and water (1:1)

Standard: Prepare as directed in 197F using USP Valproic Acid RS.

Sample: Dissolve the contents of 20 Capsules in 30 mL of Diluent in a 50-mL volumetric flask. Sonicate for 30 min to dissolve. 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 sodium chloride (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.

3 ASSAY

Procedure

Buffer: 6.8 g/L of monobasic potassium phosphate. Adjust with phosphoric acid to a pH of 3.0.

Mobile phase: Acetonitrile and Buffer (2:3)

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.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 215 nm

Column: 4.6-mm × 15-cm; 5-μm packing L1

Flow rate: 1.8 mL/min

Injection volume: 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 the labeled amount of valproic acid (C₈H₁₆O₂) in the portion of Capsules taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U= peak response from the Sample solution

r_S= peak response from the Standard solution

C_S= concentration of USP Valproic Acid RS in the Standard solution (mg/mL)

C_U= nominal concentration of valproic acid in the Sample solution (mg/mL)

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Change to read:

Dissolution 〈711〉

Test 1

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 TS to a pH of 7.5); 500 mL, degassed

Apparatus 2: 50 rpm, with sinkers

Times: 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 the Standard stock solution and Medium

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-μm pore size. Replace the volume withdrawn with an equal volume of Medium previously heated at 37.0 ± 0.5°.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 4.6-mm × 15-cm; 5-μm packing L1

Flow rate: 1.8 mL/min

Injection volume: 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 concentration (C_i) of valproic acid (C₈H₁₆O₂) in the sample withdrawn from the vessel at each time point (i):

Result_i = (r_U/r_S) × C_S

r_U= peak response from the Sample solution

r_S= peak response from the Standard solution

C_S= concentration of the Standard solution (mg/mL)

Calculate the percentage of the labeled amount of valproic acid (C₈H₁₆O₂) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

Result₂ = [(C₂ × V) + (C₁ × V_S )] × (1/L) × 100

Result₃ = {(C₃ × V) + [(C₂ + C₁ ) × V_S ]} × (1/L) × 100

C_i = concentration of valproic acid in the portion of sample withdrawn at the specified time point (mg/mL)

V = volume of Medium, 500 mL

L = label claim (mg/Capsule)

V_S = volume of the Sample solution withdrawn at each time point and replaced with Medium (mL)

Tolerances: See Table 1.

Table 1

The percentage of the labeled amount of valproic acid (C H O ) dissolved at each time point conforms to Dissolution 〈711〉, Acceptance Table 2.

Test 2: If the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 2.

Procedure A

Medium: 0.05 M 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 2 N sodium hydroxide to a pH of 7.5); 500 mL

Apparatus 2: 50 rpm, contents of the Capsule

Time: 15 min

Standard solution A: 0.036 mg/mL of USP Valproic Acid RS in Medium. A volume of acetonitrile not exceeding 10% of the total volume may be used to dissolve the valproic acid.

Sample solution A: Pass a portion of the solution under test through a suitable filter of 0.45-μm pore size.

Procedure B

Medium: 0.05 M 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 2 N sodium hydroxide to a pH of 7.5); 900 mL

Apparatus 2: 50 rpm, with wire helix sinkers

Time: 4 h

Buffer A: 0.5 g/L of citric acid and 0.4 g/L of dibasic sodium phosphate in water

Buffer B: 6.8 g/L of monobasic potassium phosphate and 1.7 g/L of sodium hydroxide in water; adjusted with phosphoric acid to a pH of 7.4

Mobile phase: Acetonitrile, Buffer A, and Buffer B (30:35:35); adjusted with phosphoric acid to a pH of 3.0

Standard solution B: 0.13 mg/mL of USP Valproic Acid RS in Medium. A volume of acetonitrile not exceeding 10% of the total volume may be used to dissolve the valproic acid.

Sample solution B: Pass a portion of the solution under test through a suitable filter of 0.45-μm pore size.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 3.9-mm × 15-cm; 4-μm packing L11

Flow rate: 1.2 mL/min

Injection volume: 200 μL for Standard solution A and Sample solution A; 50 μL for Standard solution B and Sample solution B

System suitability

Sample: Standard solution B

Suitability requirements

Tailing factor: NMT 2.0 for valproic acid

Relative standard deviation: NMT 2.0% for valproic acid

Analysis

Samples: Standard solution A, Sample solution A, Standard solution B, and Sample solution B

Calculate the percentage of the labeled amount of valproic acid (C₈H₁₆O₂) dissolved at each time point:

Result = (r_U/r_S) × (C_S/L) × V × 100

r_U= peak response from Sample solution A or Sample solution B

r_S= peak response from Standard solution A or Standard solution B

C_S= concentration of Standard solution A or Standard solution B (mg/mL)

L = label claim (mg/Capsule)

V = volume of Medium; 500 mL for Sample solution A, 900 mL for Sample solution B

Tolerances: NMT 20% of the labeled amount of valproic acid (C₈H₁₆O₂) is dissolved in 15 min (Sample solution A); NLT 80% (Q) of the labeled amount of valproic acid (C₈H₁₆O₂) is dissolved in 4 h (Sample solution B). The percentage of the labeled amount of valproic acid (C₈H₁₆O₂) dissolved at 4 h conforms to Dissolution 〈711〉, Acceptance Table 1.

Test 3: If the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 3.

Medium

Acid stage medium: 0.08 N hydrochloric acid TS; 900 mL

Buffer stage medium: Phosphate buffer, pH 7.5 (6.8 g/L of monobasic potassium phosphate and 1.6 g/L of sodium hydroxide in water, prepared as follows. Transfer suitable quantities of monobasic potassium phosphate and sodium hydroxide to a suitable volumetric flask. Dissolve in 83% of the flask volume of water and adjust with 0.1 N hydrochloric acid, if necessary, to a pH of 7.5. Dilute the resulting solution with water to volume.); 900 mL

Times

Acid stage: 2 h

Buffer stage: 4 h

Apparatus 2: 50 rpm, with sinkers

Buffer: 0.25 g/L of citric acid, 0.2 g/L of anhydrous dibasic sodium phosphate, 3.4 g/L of monobasic potassium phosphate, and 0.85 g/L of sodium hydroxide in water

Mobile phase: Acetonitrile and Buffer (45:55); mixed, degassed, and adjusted with phosphoric acid to a pH of 2.5

Standard solution: 0.14 mg/mL of USP Valproic Acid RS prepared as follows. Transfer a portion of USP Valproic Acid RS to a suitable volumetric flask. Dissolve in methanol using 5.0% of the final volume. Dilute with Buffer stage medium to final volume and mix.

Sample solutions

Acid stage sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-μm pore size, discarding the first 3 mL of filtrate.

Buffer stage sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-μm pore size, discarding the first 3 mL of filtrate.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 3.9-mm × 15-cm; 4-μm packing L11

Flow rate: 1 mL/min

Injection volume: 50 μL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution, Acid stage sample solution, and Buffer stage sample solution

Calculate the percentage of the labeled amount of valproic acid (C₈H₁₆O₂) dissolved at each time point:

Result = (r_U/r_S) × (C_S/L) × V × 100

r_U= peak response from the Acid stage sample solution or the Buffer stage sample solution

r_S= peak response from the Standard solution

C_S= concentration of the Standard solution (mg/mL)

L = label claim (mg/Capsule)

V = volume of the Acid stage medium or the Buffer stage medium, 900 mL

Tolerances: The requirements for the Acid stage and the Buffer stage must be met.

Acid stage: NMT 30% (Q) of the labeled amount of valproic acid (C₈H₁₆O₂) is dissolved in 2 h (Acid stage sample solution). The percentage of the labeled amount of valproic acid (C₈H₁₆O₂) dissolved at 2h conforms to Table 2.

Table 2

Buffer stage: NLT 80% (Q) of the labeled amount of valproic acid (C H O ) is dissolved in 4 h (Buffer stage sample solution). The percentage of the labeled amount of valproic acid (C H O ) dissolved at 4 h conforms to Dissolution 〈711〉, Acceptance Table 2.

Test 4: If the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 4.

Medium: 0.05 M phosphate buffer, pH 7.5 (6.8 g/L of monobasic potassium phosphate in water; adjusted with 2 N sodium hydroxide to a pH of 7.5); 500 mL

Apparatus 2: 50 rpm

Times: 2, 4, and 8 h

Buffer A: 0.5 g/L of citric acid and 4 g/L of dibasic sodium phosphate in water

Buffer B: 6.8 g/L of monobasic potassium phosphate and 1.7 g/L of sodium hydroxide in water; adjusted with phosphoric acid to a pH of 7.4

Mobile phase: Acetonitrile, Buffer A, and Buffer B (30:35:35); adjusted with phosphoric acid to a pH of 3.0

Standard solution: 0.25 mg/mL of USP Valproic Acid RS in Medium

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-μm pore size.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 3.9-mm × 15-cm; 4-μm packing L11

Column temperature: 30°

Flow rate: 1.2 mL/min

Injection volume: 50 μL

Run time: NLT 1.5 times the retention time of valproic acid

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 concentration (C_i) of valproic acid (C₈H₁₆O₂) in the sample withdrawn from the vessel at each time point (i):

Result_i = (r_U/r_S) × C_S

r_U= peak response from the Sample solution

r_S= peak response from the Standard solution

C_S= concentration of the Standard solution (mg/mL)

Calculate the percentage of the labeled amount of valproic acid (₈H₁₆O₂) dissolved at each time point (i):

Result₁ = C₁ × V₁ × (1/L) × 100

Result₂ = {[C₂ × (V − V_s)] + (C₁ × V_s )} × (1/L) × 100

Result₃ = ({C₃ × [V − (2 × V_s )]} + [(C₂ + C₁) × Vs]) × (1/L) × 100

C_i = concentration of valproic acid in the portion of sample withdrawn at the specified time point (mg/mL)

V = volume of Medium, 500 mL

L = label claim (mg/Capsule)

V_s = volume of the Sample solution withdrawn at each time point (mL)

Tolerances: See Table 3.

Table 3

The percentage of the labeled amount of valproic acid (C H O ) dissolved at each time point conforms to Dissolution 〈711〉, Acceptance

Table 4.

Test 5: If the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 5.

Medium: 0.05 M 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 2 N sodium hydroxide to a pH of 7.5); 900 mL, deaerated

Apparatus 2: 50 rpm with suitable sinkers

Times: 1 and 4 h

Buffer A: 0.5 g/L of citric acid and 0.4 g/L of dibasic sodium phosphate in water

Buffer B: 6.8 g/L of monobasic potassium phosphate and 1.7 g/L of sodium hydroxide in water; adjusted with phosphoric acid to a pH of 7.4

Mobile phase: Acetonitrile, Buffer A, and Buffer B (30:35:35); adjusted with phosphoric acid to a pH of 3.0

Standard solution: (L/900) mg/mL of USP Valproic Acid RS in Medium, where L is the label claim in mg/Capsule

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-μm pore size, discarding the first 2–3 mL of the filtrate.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 3.9-mm × 15-cm; 4-μm packing L11

Flow rate: 1.2 mL/min

Injection volume: 50 μL

Run time: NLT 1.5 times the retention time of valproic acid

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 concentration (C_i) of valproic acid (C₈H₁₆O₂) in the sample withdrawn from the vessel at each time point (i):

Result = (r_U/r_S) × C_S

r_U= peak response from the Sample solution

r_S= peak response from the Standard solution

C_S= concentration of the Standard solution (mg/mL)

Calculate the percentage of the labeled amount of valproic acid (C₈H₁₆O₂) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

Result₂ = {[C₂ × (V − V_S)] + (C₁ × V_S)} × (1/L) × 100

C_i = concentration of valproic acid in the portion of sample withdrawn at the specified time point (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Capsule)

V_S = volume of the Sample solution withdrawn at each time point (mL)

Tolerances: See Table 4.

Table 4

The percentage of the labeled amount of valproic acid (C H O ) dissolved at each time point conforms to Dissolution 〈711〉, Acceptance

Table 2.

Test 6: If the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 6.

Medium: 0.05 M phosphate buffer pH 7.5 (dissolve 6.8 g of monobasic potassium phosphate and 1.64 g of sodium hydroxide in each liter of water; adjust with 2 N sodium hydroxide to a pH of 7.5); 900 mL

Apparatus 2: 50 rpm, with wire helix sinkers

Times: 0.5, 1.5, and 4 h

Buffer A: Dissolve 0.5 g of citric acid and 0.4 g of dibasic sodium phosphate in each liter of water.

Buffer B: Dissolve 6.8 g of monobasic potassium phosphate and 1.7 g of sodium hydroxide in each liter of water; adjust with phosphoric acid to a pH of 7.4.

Mobile phase: Acetonitrile, Buffer A, and Buffer B (30:35:35). Adjust with phosphoric acid to a pH of 3.0.

Standard stock solution: 1.62 mg/mL of USP Valproic Acid RS in Medium prepared as follows. Transfer an appropriate amount of USP

Valproic Acid RS into a suitable volumetric flask. Add 10% of flask volume of acetonitrile and sonicate to dissolve. Add about 60% of flask volume of Medium. Allow the solution to reach room temperature. Dilute with Medium to volume.

Standard solution: 0.13 mg/mL of USP Valproic Acid RS in Medium

Sample solution: At the specified Times, withdraw and pass a portion of the solution under test through a suitable filter of 0.45-μm pore size.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 3.9-mm × 15-cm; 4-μm packing L11

Flow rate: 1.2 mL/min

Injection volume: 50 μL

Run time: NLT 2 times the retention time of valproic acid

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C_i) of valproic acid (C₈H₁₆O₂) in the sample withdrawn from the vessel at each time point (i):

Result_i = (r_U/r_S) × C_S

r_U= peak response of valproic acid from the Sample solution

r_S= peak response of valproic acid from the Standard solution

C_S= concentration of USP Valproic Acid RS in the Standard solution (mg/mL)

Calculate the percentage of the labeled amount of valproic acid (C₈H₁₆O₂) dissolved at each time point (i):

Result₁ = C₁ × V₁ × (1/L) × 100

Result₂ = [(C₂ × V) + (C₁ × V_S)] × (1/L) × 100

Result₃ = {(C₃ × V) + [(C₂ + C₁ ) × V_S]} × (1/L) × 100

C_i = concentration of valproic acid in the portion of sample withdrawn at time point i (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Capsule)

V_S = volume of the Sample solution withdrawn at each time point and replaced with Medium (mL)

Tolerances: See Table 5.

Table 5

The percentage of the labeled amount of valproic acid (C H O ) dissolved at the times specified conforms to Dissolution 〈711〉,

Acceptance Table 4.▲ (RB 1-Nov-2021)

Uniformity of Dosage Units 〈905〉: Meet the requirements

5 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight, light-resistant containers at controlled room temperature.

Labeling: Divalproex Sodium Delayed-Release Capsules may be swallowed whole or may be administered by carefully opening the Capsule and sprinkling 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. 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〉

USP Valproic Acid RS