Glimepiride

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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C₂₄H₃₄N₄O₅S 490.62

1H-Pyrrole-1-carboxamide, 3-ethyl-2,5-dihydro-4-methyl-N-[2-[4-[[[[(4-methylcyclohexyl)amino]carbonyl]amino]sulfonyl]phenyl]ethyl]-2-oxo-,trans-;

1-[[4-[2-(3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea CAS RN®: 93479-97-1;

UNII: 6KY687524K.

1 DEFINITION

Glimepiride contains NLT 98.0% and NMT 102.0% of glimepiride (C₂₄H₃₄N₄O₅S), calculated on the anhydrous basis.

2 IDENTIFICATION

Change to read:

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K (CN 1-May-2020) [Note—Methods described in 〈197K〉 or 〈197A〉 may be used.]

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

3.1 Procedure

Mobile phase: Dissolve 0.5 g of monobasic sodium phosphate in 500 mL of water. Adjust with phosphoric acid to a pH of 2.1–2.7, and add 500 mL of acetonitrile.

Diluent: Acetonitrile and water (4:1)

Standard solution: 0.2 mg/mL of USP Glimepiride RS in Diluent

System suitability stock solution: 0.1 mg/mL each of USP Glimepiride Related Compound B RS, USP Glimepiride Related Compound C RS, and USP Glimepiride Related Compound D RS in Diluent

System suitability solution: Dilute 1 mL of the System suitability stock solution with the Standard solution to 50 mL.

Sample solution: 0.2 mg/mL of Glimepiride in Diluent. [Note—Keep the Sample solution at a temperature not exceeding 12°, and store it no longer than 15 h.]

3.2 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 228 nm

Column: 4-mm × 25-cm or 4.6-mm × 25-cm; 4- or 5-μm packing L1

Flow rate: 1 mL/min

Injection volume: 20 μL

3.3 System suitability

Samples: Standard solution and System suitability solution

[Note - See Table 1 for relative retention times.]

3.4 Suitability requirements

Resolution: NLT 4.0 between glimepiride related compound B and glimepiride related compound C, System suitability solution

Relative standard deviation: NMT 0.73%, Standard solution

3.5 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of glimepiride (C₂₄H₃₄N₄O₅S) in the portion of Glimepiride 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 Glimepiride RS in the Standard solution (mg/mL)

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

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

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.2%

4.1 Limit of cis-Isomer (Glimepiride Related Compound A)

Mobile phase: Transfer 100 mL of isopropyl alcohol to a 1-L volumetric flask, add 1 mL of glacial acetic acid, and dilute with hexane to volume.

System suitability stock solution: Dissolve 1 mg of USP Glimepiride Related Compound A RS in 1 mL of methylene chloride. Add 3 mL of Mobile phase, and mix.

System suitability solution: Transfer 10 mg of USP Glimepiride RS into a 20-mL volumetric flask, dissolve in 5 mL of methylene chloride, and dilute with Mobile phase to volume. Transfer 5 mL of this solution to a separate flask, add 50 μL of the System suitability stock solution, and mix.

Sample solution: Transfer 10 mg of Glimepiride into a 20-mL volumetric flask, dissolve in 5 mL of methylene chloride, and dilute with Mobile phase to volume.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 228 nm

Column: 3-mm × 15-cm; 5-μm packing L20

[Note - The analyses could also be performed with 4.6-mm × 15-cm, 4.6-mm × 25-cm, 4-mm × 12.5-cm, or 4-mm × 25-cm columns containing packing L20. It is recommended that the flow rate be adjusted to about 1.1 mL/min for a 4.6-mm column and to about 0.8 mL/min for a 4.0-mm column.]

Flow rate: 0.5 mL/min

Injection volume: 10 μL

System suitability

Sample: System suitability solution

[Note - The relative retention times for glimepiride cis-isomer and glimepiride are 0.9 and 1.0, respectively.]

Suitability requirements

Signal-to-noise ratio: NLT 15 for the glimepiride cis-isomer peak

Peak-to-valley ratio: NLT 2.0 for glimepiride cis-isomer and glimepiride

Analysis

Sample: Sample solution

Calculate the percentage of glimepiride cis-isomer in the portion of Glimepiride taken:

Result =r_cis/(r_cis + r_G) × 100

r_cis = peak area of glimepiride cis-isomer from the Sample solution

r_G = peak area of glimepiride from the Sample solution

Acceptance criteria: NMT 0.8%

4.2 Organic Impurities

Mobile phase, Diluent, Standard solution, System suitability solution, Sample solution, and System suitability: Proceed as directed in the Assay.

Diluted sample solution 1: Dilute 5.0 mL of the Sample solution with Diluent to 100.0 mL. Dilute 5.0 mL of the solution obtained with Diluent to 50.0 mL. This solution contains about 0.001 mg/mL of glimepiride.

Diluted sample solution 2: Dilute 1.0 mL of Diluted sample solution 1 with Diluent to 10.0 mL.

Chromatographic system: Proceed as directed in the Assay, except for the Run time.

Run time: 2.5 times the retention time of the glimepiride peak

Analysis

Samples: Sample solution, Diluted sample solution 1, and Diluted sample solution 2

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

Result = (r_U/r_S) × (C_S/C_U)) × 100

r_U = peak response of each impurity from the Sample solution

r_S = peak response of glimepiride from Diluted sample solution 1

C_S = concentration of Glimepiride in Diluted sample solution 1 (mg/mL)

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

Acceptance criteria: See Table 1. Disregard any peak with an area less than that of the glimepiride peak from Diluted sample solution 2.

Table 1

5 SPECIFIC TESTS

Water Determination 〈921〉, Method I, Method Ic

Sample solution: Dissolve 0.25 g of Glimepiride in dimethylformamide previously dried over a 2-mm molecular sieve with 0.4-nm pore size, and dilute with the same solvent to 5.0 mL.

Analysis: Use 1.0 mL of the Sample solution. Perform a blank determination, using 1.0 mL of the solvent.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Store in well-closed containers, at a temperature not exceeding 25°.

USP Reference Standards 〈11〉

USP Glimepiride RS

USP Glimepiride Related Compound A RS

Glimepiride cis-isomer;

1-[[p-[2-(3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]phenyl]sulfonyl]-3-(cis-4-methylcyclohexyl)urea.

C₂₄H₃₄N₄O₅S 490.62

USP Glimepiride Related Compound B RS

Glimepiride sulfonamide;

3-Ethyl-4-methyl-2-oxo-N-(4-sulfamoylphenethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide.

C₁₆H₂₁N₃O₄S 351.42

USP Glimepiride Related Compound C RS

Glimepiride urethane;

Methyl ({4-[2-(3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamido)ethyl]phenyl}sulfonyl)carbamate.

C₁₈H₂₃N₃O₆S  409.46

USP Glimepiride Related Compound D RS

Glimepiride 3-isomer;

1-[[m-[2-(3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea.

C₂₄H₃₄N₄O₅S 490.62