Aprepitant

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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C₂₃H₂₁F₇N₄O₃  534.43

3H-1,2,4-Triazol-3-one, 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl] ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-;

3-[[(2R,3S)-3-(p-Fluorophenyl)-2-[[(R)-α-methyl-3,5-bis(trifluoromethyl)benzyl)oxy]morpholino]methyl]-12-1,2,4-triazolin-5-one;

3-[[(2R,3S)-2-[(R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl) morpholino]methyl]-1H-1,2,4-triazol-5(4H)-one;

5-[[(2R,3S)-2-[(R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one CAS RN®: 170729-80-3; UNII: 1NF15YR6UY.

1 DEFINITION

Aprepitant contains NLT 98.0% and NMT 102.0% of aprepitant (C₂₃H₂₁F₇N₄O₃), calculated on the anhydrous and solvent-free basis.

2 IDENTIFICATION

Change to read:

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 1974, 197K, or 197M (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

3.1 PROCEDURE

Dilute phosphoric acid: Dilute 1 mL of phosphoric acid with water to 1 L.

Mobile phase: Acetonitrile and Dilute phosphoric acid (48:52)

Diluent: Acetonitrile and Dilute phosphoric acid (50:50)

Standard solution: 0.2 mg/mL of USP Aprepitant RS in Diluent; sonicate as needed

Sample solution: 0.2 mg/mL of Aprepitant in Diluent; sonicate as needed

Chromatographic system

(See omatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

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

Column temperature: 35°

Flow rate: 1.5 mL/min

Injection volume: 20 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 0.73%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of aprepitant (C₂₃H₂₁F₇N₄O₃) in the portion of Aprepitant 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 the Standard solution (mg/mL)

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

Acceptance criteria: 98.0%-102.0%, on the anhydrous and solvent-free basis

4 IMPURITIES

4.1 RESIDUE ON IGNITION (281)

NMT 0.1%

4.2 ORGANIC IMPURITIES

Dilute phosphoric acid and Diluent: Proceed as directed in the Assay.

Solution A: Dilute phosphoric acid

Solution B: Acetonitrile

Mobile phase: See Table 1.

Table 1

Return to original conditions and re-equilibrate the system.

System suitability solution: 2.0 mg/mL of USP Aprepitant RS and 0.003 mg/mL of USP Desfluoro Aprepitant RS in Diluent, using sonication

as necessary to dissolve

Sensitivity solution: 0.001 mg/mL of USP Aprepitant RS in Diluent

Standard solution: 0.003 mg/mL of USP Aprepitant RS in Diluent, using sonication as necessary to dissolve

Sample solution: 2.0 mg/mL of Aprepitant in Diluent, using sonication as necessary to dissolve

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

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

Column temperature: 35°

Flow rate: 1.0 mL/min

Injection volume: 10 µL

System suitability

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

Suitability requirements

Resolution: NLT 3.0 between the desfluoro aprepitant and aprepitant peaks, System suitability solution

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

Relative standard deviation: NMT 5.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each individual impurity in the portion of Aprepitant taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response for each impurity from the Sample solution

r_S = peak response for aprepitant from the Standard solution

C_S = concentration of USP Aprepitant RS in the Standard solution (mg/mL)

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

Acceptance criteria: See Table 2. Disregard any peak below 0.05%.

Table 2

4.3 LIMIT OF S,R,S-ENANTIOMER (if present)

[NOTE-Perform this test if this impurity is possible from the manufacturing process.]

Mobile phase: Hexane and dehydrated alcohol (90:10)

System suitability solution: 0.08 mg/mL of USP Aprepitant RS and 0.08 mg/mL of USP Aprepitant Related Compound B RS in Mobile phase

Sample solution: 0.5 mg/mL of Aprepitant in Mobile phase

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 4.6-mm x 25-cm; packing L51

Column temperature: 30°

Flow rate: 0.5 mL/min

Injection volume: 20 µL

System suitability

Sample: System suitability solution

Suitability requirements

Resolution: Greater than 2.0 between the enantiomer peaks. [NOTE-The elution order is the S,R,S-enantiomer followed by the aprepitant peak, which is the R,S,R-enantiomer.]

Analysis

Sample: Sample solution

Calculate the percentage of the S,R,S-enantiomer in the portion of Aprepitant taken:

Result = (r_U/r_T) x 100

r_U = peak response of the S,R,S-enantiomer

r_T = sum of the peak responses of aprepitant and the S,R,S-enantiomer

Acceptance criteria: NMT 0.10% of the S,R,S-enantiomer

5 SPECIFIC TESTS

WATER DETERMINATION, Method laor/c(921): NMT 0.5%

OPTICAL ROTATION, Specific Rotation(781S)

Sample solution: 10 mg/mL in methanol

Acceptance criteria: +66.0° to +71.0°

6 ADDITIONAL REQUIREMENTS

6.1 PACKAGING AND STORAGE

Preserve in well-closed containers, protected from light. Store at room temperature.

6.2 USP REFERENCE STANDARDS (11)

USP Aprepitant RS

USP Aprepitant Related Compound B RS

S,R,S-Enantiomer: 3-[[(2S,3R)-2-[(S)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl) morpholino]methyl]-1H-1,2,4-triazol-5(4H)-one.

C₂₃H₂₁F₇N₄O₃  534.43

USP Desfluoro Aprepitant RS

5-[[(2R,3S)-2-[(R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]-3-phenylmorpholino]methyl]-2H-1,2,4-triazol-3(4H)-one.

C₂₃H₂₂F₆N₄O₃  516.44