Lamotrigine

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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C₉H₇Cl₂N₅ 256.09

1,2,4-Triazine-3,5-diamine, 6-(2,3-dichlorophenyl);

3,5-Diamino-6-(2,3-dichlorophenyl)-as-triazine CAS RN®: 84057-84-1; UNII: U3H27498KS.

1 DEFINITION

Lamotrigine contains NLT 98.0% and NMT 102.0% of C₉H₇Cl₂N₅, calculated on the dried basis.

2 IDENTIFICATION

Change to read:

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

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

Diluent: Dilute 8.5 mL of hydrochloric acid with water to 1 L (0.1 M hydrochloric acid).

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

Solution A: Triethylamine and Buffer (1:150). Adjust with phosphoric acid to a pH of 2.0.

Solution B: Acetonitrile

Mobile phase: See Table 1.

Table 1

Standard solution: 0.2 mg/mL of USP Lamotrigine RS prepared as follows. Transfer the required amount of USP Lamotrigine RS to a suitable volumetric flask, and add 5% of the final volume with methanol to facilitate dissolution. Dilute with Diluent to volume.

Sample solution: 0.2 mg/mL of Lamotrigine prepared as follows. Transfer the required amount of lamotrigine to a suitable volumetric flask, and add 5% of the final volume with methanol to facilitate dissolution. Dilute with Diluent to volume.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 270 nm

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

Column temperature: 35°

Flow rate: 1 mL/min

Injection size: 10 μL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 1.5%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of lamotrigine (C₉H₇Cl₂N₅) in the portion of Lamotrigine 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 Lamotrigine RS in the Standard solution (mg/mL)

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

Acceptance criteria: 98.0%–102.0% on the dried basis

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.1%

Limit of Lamotrigine Related Compound B

Diluent, Solution A, and Sample solution: Prepare as directed in the Assay.

Mobile phase: Acetonitrile and Solution A (35:65)

System suitability stock solution: 0.2 mg/mL of USP Lamotrigine RS prepared as follows. Transfer the required amount of USP Lamotrigine RS to a suitable volumetric flask, and add 5% of the final volume with methanol to facilitate dissolution. Dilute with Diluent to volume.

Standard stock solution: 0.01 mg/mL of USP Lamotrigine Related Compound B RS prepared as follows. Transfer the required amount of USP

Lamotrigine Related Compound B RS to a volumetric flask. Add 80% of the flask volume of methanol, and acidify with 1% of the flask volume of hydrochloric acid. Allow to cool, and dilute with methanol to volume. Dilute a portion of this solution with Diluent.

System suitability solution: 1 μg/mL of lamotrigine related compound B from the Standard stock solution in System suitability stock solution

Standard solution: 5 μg/mL of lamotrigine related compound B from the Standard stock solution in Diluent

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: 35°

Flow rate: 1 mL/min

Injection size: 10 μL

Run time: 2 times the retention time of lamotrigine related compound B

System suitability

Sample: System suitability solution

[Note—Identify the peaks in the System suitability solution, taking into account that lamotrigine is unretained, eluting at or near the solvent front.]

Suitability requirements

Tailing factor: NMT 2.0 for the lamotrigine related compound B peak

Relative standard deviation: NMT 5.0% for the lamotrigine related compound B peak

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of lamotrigine related compound B in the portion of Lamotrigine taken:

Result = (r_U/r_S)x(C_S/C_U) × 100

r_U = peak response for lamotrigine related compound B from the Sample solution

r_S = peak response for the lamotrigine related compound B from the Standard solution

C_S = concentration of USP Lamotrigine Related Compound B RS in the Standard solution (μg/mL)

C_U = concentration of Lamotrigine in the Sample solution (μg/mL)

Acceptance criteria: NMT 0.1% of lamotrigine related compound B. [Note—Lamotrigine related compound D, if present, will elute at a retention time of about 1.5 relative to lamotrigine related compound B. Disregard this peak as it is quantified in the test for Organic Impurities.]

Organic Impurities

Diluent, Buffer, Solution A, Solution B, Mobile phase, Sample solution, and Chromatographic system: Proceed as directed in the Assay.

System suitability stock solution: 0.2 mg/mL of USP Lamotrigine RS prepared as follows. Transfer the required amount of USP Lamotrigine

RS to a suitable volumetric flask, and add 5% of the final volume with methanol to facilitate dissolution. Dilute with Diluent to volume.

Impurities stock solution: 0.1 mg/mL of each of USP Lamotrigine Related Compound C RS and USP Lamotrigine Related Compound D RS prepared as follows. Transfer suitable quantities of the Reference Standards to a suitable volumetric flask. Add an amount of methanol equal to 80% of the flask volume, and acidify with 1% of the flask volume of hydrochloric acid. Allow to cool. Dilute with methanol to volume.

System suitability solution: 0.5 μg/mL each of lamotrigine related compound C and lamotrigine related compound D from Impurities stock solution in System suitability stock solution

System suitability

Sample: System suitability solution

[Note—Refer to Table 2 for relative retention times.]

Suitability requirements

Resolution: NLT 2.0 between lamotrigine and lamotrigine related compound C peaks

Analysis

Samples: Diluent and Sample solution

[Note—Disregard any peak that may be present in the chromatogram of the Diluent injection. Disregard any peak due to lamotrigine related compound B, because it is quantified in the test for Limit of Lamotrigine Related Compound B.]

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

Result = (r_U/r_S) × (1/F) × 100

r_U = peak response for each impurity from the Sample solution

r_S = peak response for the lamotrigine peak from the Sample solution

F = relative response factor for each impurity from Table 2

Acceptance criteria: See Table 2.

Table 2

^a 3-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-5(4H)-one.

^b 2,3-Dichlorobenzoic acid.

^c Included only for identification.

^d N-[5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl]-2,3-dichlorobenzamide.

5 SPECIFIC TESTS

Loss on Drying 〈731〉: Dry a sample at 105° for 3 h: it loses NMT 0.5% of its weight.

5.1 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers. Store at room temperature.

USP Reference Standards 〈11〉

USP Lamotrigine RS

USP Lamotrigine Related Compound B RS

2,3-Dichlorobenzoic acid.

C₇H₄Cl₂O₂ 191.01

USP Lamotrigine Related Compound C RS

3-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-5(4H)-one.

C₉H₆Cl₂N₄O 257.08

USP Lamotrigine Related Compound D RS

N-[5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl]-2,3-dichlorobenzamide.

C₁₆H₉Cl₄N₅O 429.09