Repaglinide

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

Repaglinide contains NLT 98.0% and NMT 102.0% of repaglinide (C₂₇H₃₆N₂O₄), 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 System suitability solution, as obtained in the test for Enantiomeric Purity.

3 ASSAY

Procedure

Buffer: 1 g/L of monobasic potassium phosphate solution, adjusted with phosphoric acid to a pH of 2.5

Mobile phase: Methanol and Buffer (8:2)

Standard solution: 0.5 mg/mL of USP Repaglinide RS in methanol

Sample solution: 0.5 mg/mL of Repaglinide in methanol

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 240 nm

Column: 4.6-mm × 12.5-cm; 5-µm packing L1

Column temperature: 45°

Flow rate: 1 mL/min

Injection volume: 10 µL

System suitability

Sample: Standard solution

Suitability requirements:

Relative standard deviation: NMT 0.73%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of repaglinide (C₂₇H₃₆N₂O₄) in the portion of Repaglinide taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

rᵤ = peak response from the Sample solution

rₛ = peak response from the Standard solution

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

Cᵤ = concentration of the Sample solution (mg/mL)

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

4 IMPURITIES

Residue on Ignition 〈281〉

Ignition temperature: 600° ± 25°

Acceptance criteria: NMT 0.1%

Organic Impurities

Solution A: 3 mg/mL of monobasic potassium phosphate solution, adjusted with 1 N sodium hydroxide to a pH of 7.0

Solution B: Methanol

Identification solution:

6 mg/mL of USP Repaglinide RS,

60 µg/mL of USP Repaglinide Related Compound A RS,

60 µg/mL of USP Repaglinide Related Compound B RS,

60 µg/mL of USP Repaglinide Related Compound C RS

in methanol

Sample solution: 6 mg/mL of Repaglinide in methanol

Standard solution: 0.06 mg/mL of repaglinide in methanol, from the Sample solution

Mobile phase: See Table 1

Table 1

Return to original conditions and re-equilibrate the system.

Chromatographic system

Mode: LC

Detector: UV 240 nm

Column: 4.6-mm × 12.5-cm; 5-µm packing L1

Column temperature: 45°

Flow rate: 1 mL/min

Injection volume: 5 µL

System suitability

Sample: Standard solution

Suitability requirement:

Relative standard deviation: NMT 10% of repaglinide, Standard solution

Analysis

Samples: Identification solution, Sample solution, and Standard solution

Chromatograph the Identification solution, and identify the components on the basis of their relative retention times given in Table 2.

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

Result = (rᵢ / rₛ) × (Cₛ / Cᵤ) × (1/F) × 100

rᵢ = peak response of each impurity from the Sample solution

rₛ = peak response of repaglinide from the Standard solution

Cₛ = concentration of repaglinide in the Standard solution (mg/mL)

Cᵤ = concentration of Repaglinide in the Sample solution (mg/mL)

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2

ᵃ (S)-Ethyl 2-ethoxy-4-[2-({3-methyl-1-[2-(piperidin-1-yl)phenyl]butyl}amino)-2-oxoethyl]benzoate.

Enantiomeric Purity

[Note—Protect all solutions containing repaglinide from light.]

Buffer: Dissolve 1 g of monobasic potassium phosphate in 1 L of water. If needed, adjust with 2 N sodium hydroxide or dilute phosphoric acid to pH 4.7.

Solution A: Buffer

Solution B: Acetonitrile

Mobile phase: See Table 3

[Note—Equilibrate after installation of the column as follows. Using water, slowly increase the flow rate from 0.2 mL/min to 0.5 mL/min. Maintain the flow rate at 0.5 mL/min for 5 min. The column must be washed with water for 1 h at a flow rate of 1 mL/min, and for 1 h with Mobile phase at the initial composition prior to the first analysis.]

Table 3

Return to the original conditions and re-equilibrate the system.

System suitability solution:

1.0 mg/mL of USP Repaglinide RS

0.02 mg/mL of USP Repaglinide Related Compound E RS

in methanol

Standard solution: 2.0 µg/mL of USP Repaglinide Related Compound E RS in methanol

Sample solution: 1.0 mg/mL of Repaglinide in methanol

Chromatographic system

Mode: LC

Detector: UV 240 nm

Column: 4.0-mm × 10-cm; 5-µm packing L41

Flow rate: 1.0 mL/min

Injection volume: 10 µL

System suitability

Samples: System suitability solution and Standard solution

[Note—Typical relative retention times: repaglinide 1.0; repaglinide related compound E 1.5]

Suitability requirements:

Resolution: NLT 1.5 between repaglinide and repaglinide related compound E

Relative standard deviation: NMT 5.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of repaglinide related compound E in the portion of Repaglinide taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

rᵤ = peak response of repaglinide related compound E in the Sample solution

rₛ = peak response of repaglinide related compound E in the Standard solution

Cₛ = concentration of USP Repaglinide Related Compound E RS in the Standard solution (mg/mL)

Cᵤ = concentration of Repaglinide in the Sample solution (mg/mL)

Acceptance criteria: NMT 0.2%

5 SPECIFIC TESTS

Loss on Drying 〈731〉

Analysis: Dry at 105° to constant weight

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers. Protect from light.

USP Reference Standards 〈11〉

USP Repaglinide RS

USP Repaglinide Related Compound A RS

(S)-3-Methyl-1-[2-(1-piperidinyl)phenyl]butylamine, N-acetyl-L-glutamate salt.

C₁₆H₂₆N₂ · C₅H₉NO₄ 435.6

USP Repaglinide Related Compound B RS

3-Ethoxy-4-ethoxycarbonylphenylacetic acid.

C₁₃H₁₆O₅ 252.27

USP Repaglinide Related Compound C RS

(S)-2-Ethoxy-4-[2-[[2-phenyl-1-[2-(1-piperidinyl)phenyl]ethyl]amino]-2-oxoethyl]benzoic acid.

C₃₀H₃₄N₂O₅ 486.61

USP Repaglinide Related Compound E RS

(R)-2-Ethoxy-4-[2-({3-methyl-1-[2-(piperidin-1-yl)phenyl]butyl}amino)-2-oxoethyl]benzoic acid.

C₂₇H₃₆N₂O₄ 452.59