Ethosuximide 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

Ethosuximide Capsules contain NLT 93.0% and NMT 107.0% of the labeled amount of ethosuximide (C₇H₁₁NO₂), present in the form of a solution of Ethosuximide in Polyethylene Glycol 400 or other suitable solvent.

2 IDENTIFICATION

Change to read:

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197S (CN 1-May-2020)

Standard solution: 66.7 mg/mL (USP 1-May-2019) of USP Ethosuximide RS in chloroform

Sample solution: Nominally 60 mg/mL of ethosuximide in chloroform prepared as follows. Transfer the equivalent of about 300 mg of ethosuximide from Capsules to a separator containing 50 mL of ethyl ether. Shake with three 10-mL portions of water, discarding the aqueous extracts. Add about 5 g of anhydrous sodium sulfate, swirl for 3 min, and filter through a small pledget of cotton that previously has been washed with ethyl ether into a small flask. Evaporate the ethyl ether solution at room temperature in a current of air to dryness, and dissolve the residue in 5 mL of chloroform.

Wavelength range: 3000–1650 cm−1

Analysis

Samples: Standard solution and Sample solution

Acceptance criteria: Meet the requirements

Add the following:

B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. (USP 1-May-2019)

3 ASSAY

Change to read:

Procedure

Mobile phase: Acetonitrile and water (12.5:87.5). To each liter, add 1.0 mL of glacial acetic acid.

System suitability solution: 0.062 mg/mL of USP Ethosuximide RS and 0.064 mg/mL of 2-ethyl-2-methylsuccinic acid in Mobile phase

Standard solution: 0.062 mg/mL of USP Ethosuximide RS in Mobile phase

Sample solution: Nominally 0.062 mg/mL of ethosuximide from Capsules in Mobile phase prepared as follows. Transfer 20 Capsules into a 2-L volumetric flask, dissolve in 1800 mL of Mobile phase, and dilute with Mobile phase to volume. Transfer 5.0 mL of the resulting solution to a 200-mL volumetric flask and dilute with Mobile phase to volume.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 225 nm

Column: 3.9-mm × 15-cm; 4-μm (USP 1-May-2019) packing L1

Flow rate: 1 mL/min

Injection volume: 10 μL

Run time: NLT 2 times the retention time of ethosuximide (USP 1-May-2019)

System suitability

Sample: System suitability solution

[Note—The relative retention times for ethosuximide and 2-ethyl-2-methylsuccinic acid are 1.0 and 1.3, respectively.] (USP 1-May-2019)

Suitability requirements

Resolution: NLT 3.5 between ethosuximide and 2-ethyl-2-methylsuccinic acid

Tailing factor: NMT 1.5

Relative standard deviation: NMT 1.0% (USP 1-May-2019) for ethosuximide and NMT 5.0% for 2-ethyl-2-methylsuccinic acid

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of ethosuximide (C₇H₁₁NO₂) 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 Ethosuximide RS in the Standard solution (mg/mL)

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

Acceptance criteria: 93.0%–107.0%

4 PERFORMANCE TESTS

Change to read:

Dissolution 〈711〉

Test 1: Use Dissolution 〈711〉, Procedure, Apparatus 1 and Apparatus 2, Immediate-Release Dosage Forms, Procedure for a pooled sample for

immediate-release dosage forms. (USP 1-May-2019)

Medium: pH 6.8 phosphate buffer; 900 mL

Apparatus 1: 50 rpm

Time: 30 min

Mobile phase: Acetonitrile and water (20:80)

Standard solution: USP Ethosuximide RS in Medium

Sample solution: Prepare as indicated in Dissolution 〈711〉, Procedure, Apparatus 1 and Apparatus 2, Immediate-Release Dosage Forms,

Procedure for a pooled sample for immediate-release dosage forms. Dilute with Medium to a concentration that is similar to that of the

Standard solution.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4-mm × 30-cm; packing L1

Flow rate: 1.5 mL/min

Injection volume: 50 μL

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of ethosuximide (C₇H₁₁NO₂) dissolved:

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 Ethosuximide RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Capsule)

(USP 1-May-2019)

Tolerances: NLT 80% (Q) of the labeled amount of ethosuximide (C₇H₁₁NO₂) is dissolved.

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

Medium: pH 6.8 phosphate buffer (prepared by adding 0.9 g sodium hydroxide per liter of 6.8-g/L monobasic potassium phosphate in water; adjust with sodium hydroxide to a pH of 6.8, if necessary; sonicate for about 15 min); 900 mL

Apparatus 2: 50 rpm

Time: 30 min

Mobile phase: Acetonitrile and water (12.5:87.5). To each liter, add 1.0 mL of glacial acetic acid.

Standard solution: (L/900) mg/mL of USP Ethosuximide RS prepared as follows, where L is the label claim in mg/Capsule. Transfer a suitable portion of USP Ethosuximide RS to an appropriate volumetric flask. Add 80% of the total flask volume of Medium and sonicate for NLT 5 min or until the solids are dissolved. Allow the resulting solution to cool to room temperature, and dilute with Medium.

Sample solution: Centrifuge a 10-mL aliquot of the solution under test for about 15 min. Use the supernatant.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 225 nm

Column: 3.9-mm × 15-cm; 5-μm packing L1

Flow rate: 1 mL/min

Injection volume: 50 μL

Run time: NLT 4 times the retention time of ethosuximide

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of ethosuximide (C₇H₁₁NO₂) dissolved:

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 Ethosuximide RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Capsule)

Tolerances: NLT 80% (Q) of the labeled amount of ethosuximide (C₇H₁₁NO₂) is dissolved. (USP 1-May-2019)

Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

Limit of 2-Ethyl-2-Methylsuccinic Acid

Mobile phase, System suitability solution, Chromatographic system, and System suitability: Proceed as directed in the Assay.

Standard solution: 0.026 mg/mL of 2-ethyl-2-methylsuccinic acid in Mobile phase

Sample solution: Nominally 2.5 mg/mL of ethosuximide from Capsules in Mobile phase prepared as follows. Transfer 20 Capsules into a 2-L volumetric flask, dissolve in 1800 mL of Mobile phase, dilute with Mobile phase to volume, and mix.

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of 2-ethyl-2-methylsuccinic acid in the portion of Capsules taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of 2-ethyl-2-methylsuccinic acid from the Sample solution

r_S = peak response of 2-ethyl-2-methylsuccinic acid from the Standard solution

C_S = concentration of 2-ethyl-2-methylsuccinic acid in the Standard solution (mg/mL)

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

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Change to read:

Packaging and Storage: Preserve in tight containers. Store at controlled room temperature. (USP 1-May-2019)

Add the following:

Labeling: When more than one Dissolution test is given, the labeling states the Dissolution test used only if Test 1 is not used. (USP 1-May-2019)

USP Reference Standards 〈11〉

USP Ethosuximide RS