Levetiracetam Extended-Release Tablets

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

Levetiracetam Extended-Release Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of levetiracetam (C₈H₁₄N₂O₂ ).

2 IDENTIFICATION

A. 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: 1.4 g/L of anhydrous dibasic sodium phosphate in water. Adjust with phosphoric acid to a pH of 3.5.

Mobile phase: Acetonitrile and Buffer (10:90)

Standard stock solution: 1.0 mg/mL of USP Levetiracetam RS prepared as follows. Weigh a suitable quantity of the Reference Standard into a volumetric flask. Add Mobile phase to fill 60% of flask volume and tetrahydrofuran to fill 4% of flask volume. Sonicate in cool water to dissolve. Equilibrate to room temperature. Dilute with Mobile phase to volume.

Standard solution: 0.08 mg/mL of USP Levetiracetam RS in Mobile phase from Standard stock solution. Pass a portion of the solution through a suitable filter of 0.45-μm pore size.

Sample stock solution: Nominally (L/100) mg/mL of levetiracetam from NLT 5 Tablets prepared as follows, where L is the label claim in mg/Tablet. Transfer the Tablets to a volumetric flask containing tetrahydrofuran to fill about 5% of flask volume. Stir for 30 min, and allow to stand for 5 min. Sonicate for 20 min with intermittent shaking. Add Mobile phase to fill 80% of final volume, and sonicate in cold water for 20 min with intermittent shaking. Add methanol to fill 10% of flask volume. Dilute with Mobile phase to volume. Centrifuge for 15 min, and pass a portion of the solution through a suitable filter of 0.2-μm pore size.

Afilternatively, the Sample stock solution, having a nominal concentration of 3 mg/mL of levetiracetam, may be prepared as follows. Finely grind NLT 10 Tablets, and transfer an amount equivalent to 750 mg of levetiracetam to a suitable volumetric flask. Add 18% of the flask volume of acetonitrile. Sonicate for 10 min followed by shaking using a mechanical shaker for 10 min. Add 18% of the flask volume of water, and shake for 15 min using a mechanical shaker. Allow the sample to equilibrate to room temperature, and dilute with a mixture of acetonitrile and water (50:50) to volume. Pass a portion of the solution through a suitable filter of 0.45-μm pore size.

Sample solution: Nominally 0.08 mg/mL of levetiracetam in Mobile phase from Sample stock solution

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 205 nm

Column: 4.6-mm × 25-cm; 5-μm packing L7

Temperatures

Column: 30°

Autosampler: 10°

Flow rate: 1.5 mL/min

Injection volume: 10 μL

Run time: 3 times the retention time of levetiracetam

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 percentage of the labeled amount of levetiracetam (C₈H₁₄N₂O₂ ) in the portion of Tablets taken:

Result = (r_U/r_S)x(C_S/C_U) × 100

r_U = peak response of levetiracetam from the Sample solution

r_S = peak response of levetiracetam from the Standard solution

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

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

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Change to read:

Dissolution 〈711〉

Test 1

Buffer A: Dissolve 6.8 g of potassium dihydrogen phosphate and 0.2 g of sodium hydroxide in 1 L of water. If necessary, adjust with 1 N

sodium hydroxide to a pH of 6.0.

Medium: Buffer A; 900 mL

Apparatus 1: 100 rpm

Times: 1, 2, 4, and 8 h

Buffer B: 1.4 g/L of anhydrous dibasic sodium phosphate in water. Adjust with phosphoric acid to a pH of 3.5.

Mobile phase: Acetonitrile and Buffer B (10:90)

Standard stock solution: 1.7 mg/mL of USP Levetiracetam RS in water. Sonication may be used to aid in dissolution.

Standard solution: (L/900) mg/mL of USP Levetiracetam RS in Medium from Standard stock solution, where L is the label claim in mg/Tablet. Pass a portion through a suitable filter of 0.45-μm pore size.

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 205 nm

Column: 4.6-mm × 25-cm; 5-μm packing L7

Temperatures

Column: 30°

Autosampler: 10°

Flow rate: 1.5 mL/min

Injection volume: 5 μL

Run time: 2 times the retention time of levetiracetam

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 levetiracetam (C₈H₁₄N₂O₂ ) in Medium (mg/mL) after 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 levetiracetam (C₈H₁₄N₂O₂ ) 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

Result₄ = {(C₄ × V) + [(C₃ + C₂ + C₁ ) × V_S ]} × (1/L) × 100

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

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

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

Tolerances: See Table 1.

Table 1

The percentages of the labeled amount of levetiracetam (C₈H₁₄N₂O₂ ), dissolved at the times specified, conform to Dissolution 〈711〉,

Acceptance Table 2.

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

Buffer A: Dissolve 6.8 g of potassium dihydrogen phosphate and 0.2 g of sodium hydroxide in 1 L of water. If necessary, adjust with 1 N

sodium hydroxide to a pH of 6.0.

Medium: Buffer A; 900 mL

Apparatus 1: 100 rpm

Times: 1, 2, 4, and 8 h

Buffer B: 2.82 g/L of potassium dihydrogen phosphate in water

Mobile phase: Acetonitrile and Buffer B (5:95). Adjust with phosphoric acid to a pH of 2.0.

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

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 235 nm

Columns

Guard: 4.6-mm × 1-cm, 4.6-mm × 2-cm, or 4.0-mm × 2-cm; 5-μm packing L1

Analytical: 4.6-mm × 5-cm; 5-μm packing L1

Flow rate: 0.8 mL/min

Injection volume: 10 μL

Run time: 2 times the retention time of levetiracetam

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 1.5% for

ve replicate injections

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration, C_i, of levetiracetam (C₈H₁₄N₂O₂ ) in Medium (mg/mL) after 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 levetiracetam (C₈H₁₄N₂O₂ ) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

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

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

Result₄ = ({C₄ × [V − (3 × V_S )]} + [(C₃ + C₂ + C₁ ) × V_S ]) × (1/L) × 100

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

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

V_S = volume of the Sample solution withdrawn from the Medium (mL)

Tolerances: See Table 2.

Table 2

The percentages of the labeled amount of levetiracetam (C₈H₁₄N₂O₂ ), dissolved at the times specified, conform to Dissolution 〈711〉,

Acceptance Table 2.

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

Buffer A: Dissolve 6.8 g of potassium dihydrogen phosphate and 0.5 g of sodium hydroxide in 1 L of water. Adjust to a pH of 6.0.

Medium: Buffer A; 900 mL

Apparatus 1: 100 rpm

Times: 1, 2, 4, and 8 h

Buffer B: 7.8 g/L of monobasic sodium phosphate dihydrate in water. Adjust with sodium hydroxide to a pH of 5.6.

Mobile phase: Acetonitrile and Buffer B (15:85)

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

Sample solution: Centrifuge a portion of the solution under test.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

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

Column temperature: 30°

Flow rate: 1.5 mL/min

Injection volume: 10 μL

Run time: 2 times the retention time of levetiracetam

System suitability

Sample: Standard solution

Suitability requirements

Column e

ciency: NLT 1500 theoretical plates

Relative standard deviation: NMT 2.0% for six replicate injections

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration, C_i, of levetiracetam (C₈H₁₄N₂O₂ ) in Medium (mg/mL) after 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 USP Levetiracetam RS in the Standard solution (mg/mL)

Calculate the percentage of the labeled amount of levetiracetam (C₈H₁₄N₂O₂ ) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

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

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

Result₄ = ({C₄ × [V − (3 × V_S )]} + [(C₃ + C₂ + C₁ ) × V_S ]) × (1/L) × 100

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

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

V_S = volume of the Sample solution withdrawn from the Medium (mL)

Tolerances: See Table 3.

Table 3

The percentages of the labeled amount of levetiracetam (C₈H₁₄N₂O₂ ), dissolved at the times specified, conform to Dissolution 〈711〉,

Acceptance Table 2.

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

Buffer: 6.8 g/L of monobasic potassium phosphate in water. Adjust with sodium hydroxide to a pH of 6.0.

Medium: Buffer; 900 mL

Apparatus 1: 100 rpm

Times: 1, 2, 4, and 8 h

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

Sample solution: Pass a suitable portion of the solution under test through a suitable filter of 0.45-μm pore size. Discard the first 3 mL of the filtrate. Dilute a known volume of the remaining filtrate quantitatively with Medium.

Blank: Medium

Instrumental conditions

Mode: UV

Analytical wavelength: 210 nm

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration, C_i , of levetiracetam (C₈H₁₄N₂O₂ ) in Medium (mg/mL) after time point i:

Result_i = (A_U/A_S) × C_S

A_U = absorbance of the Sample solution

A_S = absorbance of the Standard solution

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

Calculate the percentage of the labeled amount of levetiracetam (C₈H₁₄N₂O₂ ) 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

Result₄ = {(C₄ × V) + [(C₃ + C₂ + C₁ ) × V_S ]} × (1/L) × 100

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

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

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

Tolerances: See Table 4.

Table 4

The percentages of the labeled amount of levetiracetam (C₈H₁₄N₂O₂ ), dissolved at the times specified, conform to Dissolution 〈711〉,

Acceptance Table 2.

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

Medium: pH 6.0 phosphate buffer (6.8 g/L of monobasic potassium phosphate in water. Adjust with sodium hydroxide to a pH of 6.0.); 900 mL

Apparatus 1: 100 rpm

Times

For 500- and 750-mg Tablets: 1, 4, 8, and 12 h

For 1000-mg Tablets: 1, 2, 4, and 8 h

Buffer: 2.7 g/L of monobasic potassium phosphate in water

Mobile phase: Acetonitrile and Buffer (10:90)

Standard stock solution: 2.8 mg/mL of USP Levetiracetam RS in Medium prepared as follows. Transfer a suitable quantity of USP

Levetiracetam RS to a suitable volumetric flask. Dissolve in 20% of the flask volume of methanol. Dilute with Medium to volume.

Standard solution: (L/900) mg/mL of USP Levetiracetam RS in Medium from Standard stock solution, where L is the label claim in mg/Tablet

Sample solution: At each time point withdraw 1 mL of the solution under test, and pass it through a suitable filter of 0.45-μm pore size.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm × 15-cm; 5-μm packing L11

Flow rate: 1 mL/min

Injection volume

For 500- and 750-mg Tablets: 10 μL

For 1000-mg Tablets: 5 μL

Run time: 2 times the retention time of levetiracetam

System suitability

Sample: Standard solution

Suitability requirements

Column e

ciency: NLT 4000 theoretical plates

Tailing factor: NMT 1.5

Relative standard deviation: NMT 2.0% for

ve replicate injections

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of levetiracetam (C₈H₁₄N₂O₂ ) dissolved in Medium (mg/mL) after time point i:

Result = (r_U/r_S) × C_S × V × (1/L) × 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

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

V_U = volume of Medium, 900 mL

L = label claim (mg/Tablet)

Tolerances: See Table 5.

Table 5

The percentages of the labeled amount of levetiracetam (C₈H₁₄N₂O₂ ), dissolved at the times specified, conform to Dissolution 〈711〉,

Acceptance Table 2.

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

Medium: pH 6.0 phosphate buffer (6.9 g of monobasic potassium phosphate, and 0.23 g of sodium hydroxide in 1 L of water. Adjust with

sodium hydroxide or phosphoric acid to a pH of 6.0.); 900 mL

Apparatus 1: 100 rpm

Times: 1, 2, 4, and 8 h

Mobile phase: Acetonitrile and water (10:90)

Standard solution: 0.5 mg/mL of USP Levetiracetam RS in Medium prepared as follows. Transfer a suitable quantity of USP Levetiracetam RS to a suitable volumetric flask. Add 4% of the flask volume of methanol and 60% of the flask volume of the Medium. Sonicate for NLT 5 min. Dilute with Medium to volume.

Sample solution: At the end of specified time interval, withdraw a known volume of the solution from the dissolution vessel. Pass a suitable 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 230 nm

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

Column temperature: 30°

Flow rate: 0.9 mL/min

Injection volume: 10 μL

Run time: 2 times the retention time of levetiracetam

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 , of levetiracetam (C₈H₁₄N₂O₂ ) in Medium (mg/mL) after 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 levetiracetam (C₈H₁₄N₂O₂ ) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

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

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

Result₄ = ({C₄ × [V − (3 × V_S )]} + [(C₃ + C₂ + C₁ ) × V_S ]) × (1/L) × 100

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

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

V_S = volume of the Sample solution withdrawn from the solution under test (mL)

Tolerances: See Table 6.

Table 6

The percentages of the labeled amount of levetiracetam (C₈H₁₄N₂O₂ ), dissolved at the times specified, conform to Dissolution 〈711〉,

Acceptance Table 2.

Test 7: If the product complies with this procedure, the labeling indicates that it meets USP Dissolution Test 7.

Medium: Acetate buffer, pH 4.5, prepared as follows. Dissolve 3.0 g of sodium acetate in 1 L of water and add 1.4 mL of glacial acetic acid.

Adjust with 5 N sodium hydroxide or glacial acetic acid to a pH of 4.5; 230 mL.

Apparatus 3: 15 dips per min, with suitable screens

Times

For 500-mg Tablets: 1, 2, 4, and 8 h

For 750-mg Tablets: 1, 2, 4, and 10 h

For 1000- and 1500-mg Tablets: 1, 4, and 12 h (RB 1-Jan-2020)

Buffer: 13.6 g/L of monobasic potassium phosphate in water. Adjust with 5 N sodium hydroxide to a pH of 6.0.

Mobile phase: Methanol and Buffer (15:85)

Standard solution: 0.55 mg/mL of USP Levetiracetam RS in Medium. Sonication may be used to aid in dissolution.

Sample solution: Pass a suitable portion of the solution under test through a suitable filter of 0.45-μm pore size. Discard the first 5 mL.

Dilute a suitable volume of the filtrate with Medium, as needed.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 4.6-mm × 10-cm; 3-μm packing L1

Column temperature: 30°

Flow rate: 1 mL/min

Injection volume: 10 μL

Run time: 2 times the retention time of levetiracetam

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 levetiracetam (C₈H₁₄N₂O₂ ) in Medium (mg/mL) after time point i:

Result_i = (r_U /r_S ) × D × C_S

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

D = dilution factor, as needed

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

Calculate the percentage of the labeled amount of levetiracetam (C₈H₁₄N₂O₂ ) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

Result₂ = C₂ × V × (1/L) × 100 + Result

Result₃ = C₃ × V × (1/L) × 100 + Result

Result₄ = C₄ × V × (1/L) × 100 + Result

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

V = volume of Medium, 230 mL

L = label claim (mg/Tablet)

Tolerances: See Table 7and Table 8. (RB 1-Jan-2020)

Table 7

Table 8

The percentages of the labeled amount of levetiracetam (C₈H₁₄N₂O₂ ), dissolved at the times specified, conform to Dissolution 〈711〉,

Acceptance Table 2.

Test 8: If the product complies with this procedure, the labeling indicates that it meets USP Dissolution Test 8.

Medium: Phosphate buffer, pH 6.0, prepared as follows. Dissolve 6.8 g of monobasic potassium phosphate in 1 L of water. Adjust with 10 N sodium hydroxide solution to a pH of 6.0; 900 mL.

Apparatus 1: 100 rpm

Times: 1, 2, 4, and 12 h

Buffer: 0.26 g/L of monobasic potassium phosphate in water. Adjust with 20 g/L aqueous potassium hydroxide to a pH of 5.5.

Solution A: Acetonitrile and Buffer (5:95)

Mobile phase: Acetonitrile and Solution A (10:90)

Standard solution: (L/900) mg/mL of USP Levetiracetam RS in Medium, where L is the label claim in mg/Tablet. Sonicate to dissolve as needed.

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 220 nm

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

Column temperature: 20°

Flow rate: 1 mL/min

Injection volume: 5 μL

Run time: NLT 1.6 times the retention time of levetiracetam

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 1.8%

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration, C_i , of levetiracetam (C₈H₁₄N₂O₂ ) in Medium (mg/mL) after 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 levetiracetam (C₈H₁₄N₂O₂ ) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

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

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

Result₄ = ({C₄ × [V − (3 × V_S )]} + [(C₃ + C₂ + C₁ ) × V_S ]) × (1/L) × 100

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

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

V_S = volume of the Sample solution withdrawn from the Medium (mL)

Tolerances: See Table 9.

Table 9 (RB 1-Jan-2020)

The percentages of the labeled amount of levetiracetam (C₈H₁₄N₂O₂ ), dissolved at the times specified, conform to Dissolution 〈711〉,

Acceptance Table 2.

Test 9: If the product complies with this procedure, the labeling indicates that it meets USP Dissolution Test 9.

Medium: Phosphate buffer, pH 6.0, prepared as follows. Dissolve 6.8 g of monobasic potassium phosphate in 1 L of water. Adjust with 50% (w/v) potassium hydroxide solution to a pH of 6.0; 900 mL.

Apparatus 1: 100 rpm

Times: 1, 2, 4, and 12 h

Buffer: 5.0 g/L of monobasic potassium phosphate in water

Mobile phase: Acetonitrile and Buffer (15:85)

Standard solution: 0.56 mg/mL of USP Levetiracetam RS in Medium. Sonicate to dissolve as necessary.

Sample solution: Centrifuge a portion of the solution under test and use the clear supernatant. [Note—The use of a centrifuge speed of 2500 rpm for 10 min may be suitable.]

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm × 15-cm; 5-μm packing L7

Flow rate: 1.5 mL/min

Injection volume: 5 μL

Run time: NLT 2 times the retention time of levetiracetam

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 levetiracetam (C₈H₁₄N₂O₂ ) in Medium (mg/mL) after 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 levetiracetam (C₈H₁₄N₂O₂ ) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

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

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

Result₄ = ({C₄ × [V − (3 × V_S )]} + [(C₃ + C₂ + C₁ ) × V_S ]) × (1/L) × 100

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

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

V_S = volume of the Sample solution withdrawn from the Medium (mL)

Tolerances: See Table 10.

Table 10 (RB 1-Jan-2020)

The percentages of the labeled amount of levetiracetam (C₈H₁₄N₂O₂ ), dissolved at the times specified, conform to Dissolution 〈711〉,

Acceptance Table 2.

Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

Change to read:

Organic Impurities

Solution A: Dilute 2 mL of phosphoric acid with water to 1 L.

Diluent: Acetonitrile and Solution A (5:95)

Buffer: 1.4 g/L of anhydrous dibasic sodium phosphate in water. Adjust with phosphoric acid to a pH of 3.5.

Mobile phase: Acetonitrile and Buffer (5:95). To each L of the mixture, add 1 g of sodium 1-hexanesulfonate monohydrate.

System suitability solution: 0.3 mg/mL of USP Levetiracetam RS in Diluent prepared as follows. Dissolve the required amount of USP

Levetiracetam RS in 10% of the final volume of 0.1 N potassium hydroxide. Let the mixture react at room temperature for about 15 min, andvthen neutralize by adding 0.1 N hydrochloric acid at 10% of the flask volume. Dilute with Diluent to volume. [Note—This solution contains levetiracetam and levetiracetam acid.]

Standard solution: 12.5 μg/mL of USP Levetiracetam RS in water. Sonication may be used to aid in dissolution. Pass a portion of the solution through a suitable filter of 0.2-μm pore size.

Sample solution: Nominally equivalent to 2.5 mg/mL of levetiracetam in water, from a portion of crushed Tablets (NLT 20) prepared as follows. Transfer the weighed amount of crushed Tablet powder to a volumetric flask containing water to fill 80% of final volume. Sonicate in cold water for 10 min. Equilibrate to room temperature. Dilute with water to volume. Pass a portion through a suitable filter of 0.2-μm pore size.

Afilternatively, the Sample solution having a nominal concentration of 2–3 mg/mL of levetiracetam may be prepared as follows. Finely grind NLT 10 Tablets, and transfer an amount equivalent to one Tablet to a suitable volumetric flask. Add NLT 30 mL of acetonitrile. Sonicate for 10 min, and shake using a mechanical shaker for 10 min. Add NLT 30 mL of water, and shake for 15 min using a mechanical shaker.

Allow the resulting mixture to equilibrate to room temperature. Add NMT 25% of the final flask volume of acetonitrile. Dilute with water to volume. Centrifuge for 15 min, and pass a portion through a suitable filter of 0.45-μm pore size.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 205 nm

Column: 4.6-mm × 25-cm; 5-μm packing L1

Temperatures

Column: 30°

Autosampler: 10°

Flow rate: 2 mL/min

Injection volume: 20 μL

Run time: 5 times the retention time of levetiracetam

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 1.5 between levetiracetam and levetiracetam acid peaks, System suitability solution

Tailing factor: NMT 2.0, Standard solution

Relative standard deviation: NMT 5.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of any unspecified degradation product in the portion of Tablets taken:

Result = (r_U/r_S)x(C_S/C_U) × 100

r_U = peak response of each impurity from the Sample solution

r_S = peak response of USP Levetiracetam RS from the Standard solution

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

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

Acceptance criteria: See Table 11.

Table 11 (RB 1-Jan-2020)

^a (S)-2-Aminobutanamide.

^b Process impurities controlled in the drug substance. Included for identification purposes only. Not reported for the drug product, and not included in total impurities.

^c (S)-2-(2-Oxopyrrolidin-1-yl)butanoic acid.

^d (S)-N-(1-Amino-1-oxobutan-2-yl)-4-chlorobutanamide.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers. Store 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〉

USP Levetiracetam RS