Levetiracetam 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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To view the Notice from the Expert Committee that posted in conjunction with this accelerated revision, please click https://www.uspnf.com/rb-levetiracetam-tabs-20220624.

1 DEFINITION

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

2 IDENTIFICATION

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

Standard solution: 1 mg/mL solution of USP Levetiracetam RS in solution prepared as follows. Transfer a suitable quantity of USP

Levetiracetam RS to a suitable volumetric flask. Add 70% of the flask volume of acetone. Sonicate for 15 min. Dilute with acetone to volume.

Standard: Pass 10 mL of the Standard solution through a membrane filter of 0.45-μm pore size. Evaporate acetone from the filtrate completely to form crystals. Scratch the crystals. Weigh 2–4 mg of the residue and 200 mg of KBr in a mortar and pestle. Mix and grind well, and prepare the KBr pellet.

Sample solution: Transfer an amount of finely powdered Tablets (NLT 20) equivalent to 250 mg of levetiracetam to a 50-mL volumetric flask.

Add 35 mL of acetone. Sonicate for 15 min. Dilute with acetone to volume.

Sample: Pass 10 mL of the Sample solution through a membrane filter of 0.45-μm pore size. Evaporate acetone from the filtrate completely to form crystals. Scratch the crystals. Weigh 2–4 mg of the residue and 200 mg of KBr in a mortar and pestle. Mix and grind well, and prepare the KBr pellet.

Analysis: Record the spectra of the Standard and Sample between 4000 cm^-1 and 650 cm^-1.

Acceptance criteria: The spectrum of the Sample corresponds to that of the Standard.

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: 1.4 g/L of monobasic potassium phosphate and 0.6 g/L of sodium 1-heptanesulfonate, adjusted with phosphoric acid to a pH of 2.8

Mobile phase: Acetonitrile and Buffer (8:92)

Diluent: Acetonitrile and water (20:80)

Standard solution: 0.35 mg/mL of USP Levetiracetam RS in Diluent. Sonication may be used to aid dissolution.

Sample solution: Nominally 0.4 mg/mL of levetiracetam from NLT 20 Tablets, finely crushed, in Diluent. Sonication may be used to aid dissolution.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm × 25-cm; 4-μm packing L1

Flow rate: 2 mL/min

Injection volume: 10 μL

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 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)

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

Medium: Water; 900 mL

Apparatus 2: 50 rpm

Time: See Table 1.

Table 1

Buffer: 6.8 g/L of monobasic potassium phosphate, adjusted with dilute potassium hydroxide to a pH of 5.6

Mobile phase: Acetonitrile and Buffer (15:85)

Standard solution: (L/1000) mg/mL in Medium, where L is the Tablet label claim, in mg

Sample solution: Pass a portion of the solution under test though 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

Flow rate: 1.2 mL/min

Injection volume: 10 μL

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 ) dissolved:

Result = (r_U/r_S)x(C_S /L) × V × 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)

L = label claim (mg/Tablet)

V = volume of Medium, 900 mL

Tolerances: NLT 70% (Q) of the labeled amount of levetiracetam (C₈H₁₄N₂O₂ ) in 15 min for Tablets labeled to contain 250, 500, or 750 mg;

NLT 80% (Q) of the labeled amount of levetiracetam (C₈H₁₄N₂O₂ ) in 30 min for Tablets labeled to contain 1000 mg

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

Medium: Water; 900 mL, deaerate, if necessary

Apparatus 2: 50 rpm

Time: 15 min

Buffer: 1.36 g/L of monobasic potassium phosphate, adjusted with 10% potassium hydroxide to a pH of 5.0

Mobile phase: Acetonitrile and Buffer (10:90)

Standard solution: 54 μg/mL of USP Levetiracetam RS in Medium

Sample solution: Pass a portion of the solution under test through a suitable filter. Dilute an aliquot with Medium to obtain a concentration similar to that of the Standard solution.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 210 nm

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

Column temperature: 30°

Flow rate: 1.5 mL/min

Injection volume: 20 μL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution and Sample solution

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

Result = (r_U/r_S)x(C_S /L) × D × V × 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)

L = label claim (mg/Tablet)

D = dilution factor of the Sample solution

V = volume of Medium, 900 mL

Tolerances: NLT 80% (Q) of the labeled amount of levetiracetam (C₈H₁₄N₂O₂ ) is dissolved.

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

Medium: Water; 900 mL

Apparatus 2: 50 rpm

Time: 30 min

Buffer, Mobile phase, Standard solution, Sample solution, Chromatographic system, System suitability, and Analysis: Proceed as directed for Test 1.

Tolerances: NLT 80% (Q) of the labeled amount of levetiracetam (C₈H₁₄N₂O₂ ) is dissolved.

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

Medium: Water; 900 mL

Apparatus 2: 50 rpm

Time: 30 min

Buffer: 6.8 g/L of monobasic potassium phosphate

Mobile phase: Acetonitrile and Buffer (15:85)

Standard solution: 0.28 mg/mL of USP Levetiracetam RS in Medium

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-μm pore size, discarding the first 2 mL. Dilute an aliquot of the filtrate with Medium, if necessary, to obtain a concentration similar to that of the Standard solution.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 210 nm

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

Flow rate: 1 mL/min

Injection volume: 10 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 percentage of the labeled amount of levetiracetam (C₈H₁₄N₂O₂ ) dissolved:

Result = (r_U/r_S)xC_S × V × D × (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 = volume of Medium, 900 mL

D = dilution factor of the Sample solution

L = label claim (mg/Tablet)

Tolerances: NLT 85% (Q) of the labeled amount of levetiracetam (C₈H₁₄N₂O₂ ) is dissolved.

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

Medium: 0.1 N hydrochloric acid VS, deaerated; 500 mL

Apparatus 2: 50 rpm

Time: 30 min

Buffer: 1.36 g/L of monobasic potassium phosphate, adjusted with 10% w/v potassium hydroxide solution to a pH of 5.0

Mobile phase: Acetonitrile and Buffer (10:90)

Standard solution: (L/500) mg/mL in Medium, where L is the label claim in mg/Tablet. Sonication may be necessary for complete dissolution.

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.22-μm pore size and discard the first few milliliters.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

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

Flow rate: 1.5 mL/min

Temperatures

Autosampler: 10°

Column: 30°

Injection volume: 5 μL

Run time: NLT 1.6 times the retention of the levetiracetam

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution and Sample solution

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

Result = (r_U/r_S)xC_S× (1/L) × V × 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)

L = label claim (mg/Tablet)

V = volume of Medium, 500 mL

Tolerances: NLT 80% (Q) of the labeled amount of levetiracetam (C₈H₁₄N₂O₂ ) is dissolved. (RB 16-Jun-2022)

Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

Organic Impurities

Buffer: 6.8 g/L of monobasic potassium phosphate and 0.85 g/L of sodium 1-heptanesulfonate, adjusted with phosphoric acid to a pH of 2.8

Mobile phase: Acetonitrile and Buffer (5:95)

System suitability solution: 3.6 μg/mL of USP Levetiracetam RS and 3.6 μg/mL of USP Levetiracetam Related Compound B RS in Mobile phase

Standard solution: 3.6 μg/mL of USP Levetiracetam RS in Mobile phase

Sample solution: Equivalent to 1.2 mg/mL of levetiracetam from NLT 20 Tablets, finely crushed, in Mobile phase. [Note—Sonicate if necessary, and centrifuge the solution before passing through a suitable filter.]

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 200 nm

Column: 4.6-mm × 25-cm; 4-μm packing L1

Flow rate: 1 mL/min

Injection volume: 10 μL

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 2.0 between levetiracetam related compound B and levetiracetam, System suitability solution

Tailing factor: NMT 2.0, Standard solution

Relative standard deviation: NMT 10.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Tablets taken:

Result = (r_U/r_S)x(C_S/C_U) × (1/F) × 100

r_U = peak response of each impurity 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)

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2.

Table 2

^a These impurities are listed for information only; they are process impurities, which are controlled in the drug substance.

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

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

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight 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

USP Levetiracetam Related Compound B RS

(S)-2-Aminobutanamide hydrochloride.

C₄H₁₀N₂O · HCl 138.60