Aprepitant Capsules

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

Aprepitant Capsules contain NLT 95.0% and NMT 105.0% of the labeled amount of aprepitant (C₂₃H₂₁F₇N₄O₃).

2 IDENTIFICATION

2.1 A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Ultraviolet-Visible Spectroscopy: 1970

Wavelength range: 200-400 nm

Standard solution: 0.1 mg/mL of USP Aprepitant RS in methanol. Use sonication to dissolve.

Sample solution: Transfer the contents of Capsules, equivalent to 100 mg of aprepitant, to a 100-mL volumetric flask, add about 75 mL of methanol, and sonicate for about 5 min with intermittent shaking. Cool, dilute with methanol to volume, further dilute with methanol to obtain a solution containing 0.1 mg/mL of aprepitant, and pass through a nylon filter of 0.45-µm pore size.

Acceptance criteria: Meet the requirements

2.2 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 (45:55)

Standard solution: 0.05 mg/mL of USP Aprepitant RS in Mobile phase. Use sonication as necessary to dissolve.

Sample solution: Nominally 0.05 mg/mL of aprepitant in Mobile phase, prepared as follows. Mix the contents of NLT 20 Capsules, and transfer a portion of the contents, equivalent to 100 mg of aprepitant, to a 100-mL volumetric flask. Add about 75 mL of Mobile phase and sonicate for about 10 min with intermittent shaking. Cool, dilute to volume with Mobile phase, further dilute with Mobile phase to obtain a solution containing 0.05 mg/mL of aprepitant, and pass through a nylon filter of 0.45-µm pore size.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

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

Column temperature: 40°

Flow rate: 1.5 mL/min

Injection volume: 10 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of aprepitant (C₂₃H₂₁F₇N₄O₃) in the portion of Capsules 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 S

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

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

Acceptance criteria: 95.0%-105.0%

4 PERFORMANCE TESTS

Change to read:

4.1 DISSOLUTION (711).

Test 1 (ERR 1-Jun-2022)

Medium: 2.2% sodium dodecyl sulfate in water; 900 mL

Apparatus 2: 100 rpm, with sinkers. [NOTE-A suitable sinker is available from www.agilent.com, catalog number 12-3050. Proper placement of the Capsules is in the sinkers with the cap facing the fixed prong end.]

Time: 20 min

Dilute phosphoric acid: Dilute 1 mL of phosphoric acid with water to 1 L. (ERR 1-Jun-2022)

Mobile phase: Acetonitrile and Dilute phosphoric acid (50:50)

Standard solution: (L/900) mg/mL of USP Aprepitant RS in Medium, where L is the label claim in mg/Capsule. Dissolve first in a minimal

amount of methanol (using NMT 2% of the final volume) prior to diluting with Medium.

Sample solution: Pass a portion of the solution under test through a suitable filter.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm x 15-cm; 5-µm packing L7

Flow rate: 1.5 mL/min

Injection volume: 50 µL for Capsules containing 40 mg/Capsule; 10 µL for all other strengths

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of aprepitant (C₂₃H₂₁F₇N₄O₃) dissolved:

Result = (r_U/r_S) x C_S x (V/L) × 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution s

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

V = volume of Medium, 900 mL

L = label claim (mg/Capsule)

Tolerances: NLT 80% (Q) of the labeled amount of aprepitant (C₂₃H₂₁F₇N₄O₃) is dissolved.

Test 2: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.

Medium: 2.2% sodium dodecyl sulfate in water; 900 mL

Apparatus 2: 100 rpm, with wire helix sinkers or other suitable sinkers

Time: 30 min

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

Standard solution: (L/900) mg/mL of USP Aprepitant RS in Medium, where L is the label claim in mg/Capsule. Dissolve first in a minimal

amount of methanol (using NMT 2% of the final volume) prior to diluting with Medium.

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size.

Chromatographic system: Proceed as directed in the Assay, except use an autosampler temperature of 15°.

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of aprepitant (C₂₃H₂₁F₇N₄O₃) dissolved: 

Result = (r_U/r_S) x C_S x (V/L) x 100

r_U = peak response from the Sample solution

r_S= peak response from the Standard solution S

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

V = volume of Medium, 900 mL

L = label claim (mg/Capsule)

Tolerances: NLT 80% (Q) of the labeled amount of aprepitant (C₂₃H₂₁F₇N₄O₃) is dissolved.

Test 3: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3.

Medium: 2.2% sodium lauryl sulfate in water; 900 mL

Apparatus 2: 100 rpm, with suitable sinkers. Use apex vessels.

Time: 30 min

Dilute phosphoric acid: Prepare as directed in the Assay.

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

Standard stock solution: 440 µg/mL of USP Aprepitant RS in Mobile phase. Sonication may be used to promote dissolution.

Standard solution: 44 µg/mL of USP Aprepitant RS from Standard stock solution in Medium

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size. Dilute, if necessary, with Medium to a concentration similar to that of the Standard solution.

Chromatographic system

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 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of aprepitant (C₂₃H₂₁F₇N₄O₃) dissolved:

Result = (r_U/r_S) x C_S x V x D x (1/L) x 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution s

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

V = volume of Medium, 900 mL

D = dilution factor of the Sample solution

L = label claim (mg/Capsule)

Tolerances: NLT 75% (Q) of the labeled amount of aprepitant (C₂₃H₂₁F₇N₄O₃) is dissolved.

4.2 UNIFORMITY OF DOSAGE UNITS (905): Meet the requirements

5 IMPURITIES

5.1 ORGANIC IMPURITIES

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

Solution A: Acetonitrile and Dilute phosphoric acid (5:95)

Solution B: Acetonitrile and Dilute phosphoric acid (95:5)

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

Mobile phase: See Table 1.

Table 1

Return to original conditions and re-equilibrate the system for 10 min.

System suitability solution: 0.6 mg/mL of USP Aprepitant RS and 0.0012 mg/mL each of USP Desfluoro Aprepitant RS and USP Aprepitant Related Compound A RS in Diluent

Standard solution: 0.0012 mg/mL of USP Aprepitant RS in Diluent

Sample solution: Nominally 0.6 mg/mL of aprepitant, prepared as follows. Transfer the contents of Capsules, equivalent to 120 mg of aprepitant, to a 200-mL volumetric flask, add about 150 mL of Diluent, and sonicate for about 10 min with intermittent shaking. Cool, dilute with Diluent to volume, and pass through a nylon filter of 0.45-µm pore size.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

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

Column temperature: 35°

Flow rate: 1.0 mL/min

Injection volume: 10 µL

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

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

Relative standard deviation: NMT 5.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of any individual impurity in the portion of Capsules 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 aprepitant from the Standard solution 

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

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

Acceptance criteria: See Table 2.

Table 2

^a Process impurity included in the table for identification only. Process impurities are controlled in the drug substance, and are not to be reported or included in the total impurities for the drug product.

^b The diastereomers are not separated by this procedure and should be identified based on the retention time of aprepitant related compound A (R,R,R-diastereomer), which is a component of the System suitability solution.

6 ADDITIONAL REQUIREMENTS

6.1 PACKAGING AND STORAGE

Preserve in tight containers. Store at controlled room temperature.

6.2 LABELING

When more than one Dissolution test is given, the labeling states the Dissolution test used only if Test 1 is not used.

6.3 USP REFERENCE STANDARDS (11)

USP Aprepitant RS

USP Aprepitant Related Compound A RS

R,R,R-Diastereomer: 3-[[(2R,3R)-2-[(R)-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