Regorafenib

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

Regorafenib contains NLT 97.5% and NMT 101.5% of regorafenib (C₂₁H₁₅ClF₄N₄O₃), calculated on the anhydrous and solvent-free basis.

2 IDENTIFICATION

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

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

Store the solutions containing regorafenib at 2°–8° and protect from light.

Solution A: 0.1% (v/v) trifluoroacetic acid in water

Solution B: Acetonitrile and Solution A (3:97)

Mobile phase: See Table 1. Return to original conditions, and equilibrate the system for at least 5 min.

Table 1

Standard solution: 0.45 mg/mL of USP Regorafenib RS in methanol

Sample solution: 0.45 mg/mL of Regorafenib in methanol

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Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 232 nm

Column: 2.1-mm × 15-cm; 3.5-µm packing L11

Temperatures:

Autosampler: 8°

Column: 63°

Flow rate: 0.9 mL/min

Injection volume: 5 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 regorafenib (C₂₁H₁₅ClF₄N₄O₃) in the portion of Regorafenib taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

rᵤ = peak response of regorafenib from the Sample solution

rₛ = peak response of regorafenib from the Standard solution

Cₛ = concentration of USP Regorafenib RS in the Standard solution (mg/mL)

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

Acceptance criteria: 97.5%–101.5% on the anhydrous and solvent-free basis

4 IMPURITIES

Organic Impurities

Store the solutions containing regorafenib at 2°–8° and protect from light.

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

Standard stock solution: 1.5 mg/mL of USP Regorafenib RS in methanol

Standard solution: 1.5 µg/mL of USP Regorafenib RS in methanol, from Standard stock solution

System suitability solution: 4.0 µg/mL of USP Sorafenib Tosylate RS in Standard stock solution

Sensitivity solution: 0.75 µg/mL of USP Regorafenib RS in methanol, from Standard solution

Sample solution: 1.5 mg/mL of Regorafenib in methanol

System suitability

Samples: Standard solution, System suitability solution, and Sensitivity solution

[Note—The relative retention times for sorafenib and regorafenib are 0.9 and 1.0, respectively.]

Suitability requirements:

Resolution: NLT 3.0 between the sorafenib and regorafenib peaks, System suitability solution

Relative standard deviation: NMT 5.0%, Standard solution

Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

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

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

rᵢ = peak response of each impurity from the Sample solution

rₛ = peak response of regorafenib from the Standard solution

Cₛ = concentration of USP Regorafenib RS in the Standard solution (mg/mL)

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

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2. The reporting threshold is 0.05%.

Table 2

a 4-(3-Fluoro-4-{[2-(methylcarbamoyl)pyridin-4-yl]amino}phenoxy)-N-methylpicolinamide.

b N,N’-Bis{4-[2-(N-methylcarbamoyl)-4-pyridyloxy]-2-fluorophenyl}urea.

c 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}-3-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}-3-fluorophenoxy)phenoxy)-N-methylpicolinamide.

Limit of Regorafenib Related Compound A

Store the solutions containing regorafenib or regorafenib related compound A at 2°–8° and protect from light.

Solution A: Dissolve 1.5 g of potassium phosphate, monobasic and 0.5 g of potassium phosphate, dibasic in 1 L of water.

Solution B: Solution A and acetonitrile (92:8)

Mobile phase: See Table 3. Return to original conditions, and equilibrate the system for at least 10 min.

Table 3

Standard solution: 0.075 mg/mL of USP Regorafenib Related Compound A RS in tetrahydrofuran

Sample solution: 50.0 mg/mL of Regorafenib in tetrahydrofuran

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 228 nm

Column: 3.0-mm × 15-cm; 3.5-µm packing L1

Temperatures:

Autosampler: 2°–8°

Column: 50°

Flow rate: 1.0 mL/min

Injection volume: 3 µL

System suitability

Sample: Standard solution

Requirement: Relative standard deviation: NMT 10.0%

Analysis

Calculate the percentage of regorafenib related compound A in the portion of Regorafenib taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

rᵤ = peak response of regorafenib related compound A from the Sample solution

rₛ = peak response of regorafenib related compound A from the Standard solution

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

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

Acceptance criteria: NMT 0.15%

5 SPECIFIC TESTS

Water Determination 〈921〉, Method I, Method Ic

Sample: 50 mg

Test preparation: Evaporation technique

Temperature: 150°

Heating time: 3 min

Carrier gas: Nitrogen

Flow rate: 70 mL/min

Acceptance criteria: 3.2%–4.0% for monohydrate form

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers, and protect from light. Store at room temperature.

USP Reference Standards 〈11〉

USP Regorafenib RS

USP Regorafenib Related Compound A RS

4-(4-Amino-3-fluorophenoxy)-N-methylpicolinamide.

C₁₃H₁₃FN₂O₂ 261.26

USP Sorafenib Tosylate RS

1-[4-Chloro-3-(trifluoromethyl)phenyl]-3-(4-{[2-(methylcarbamoyl)pyridin-4-yl]oxy}phenyl}urea mono(4-methylbenzenesulfonate).

C₂₁H₁₆ClF₃N₄O₃ · C₇H₈O₃S 637.03 ▲ (USP 1-May-2021)