Fentanyl

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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C₂₂H₂₈N₂O   336.48 _{(ERR 1-Jan-2021)}

Propanamide, N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl];

N-(1-Phenethylpiperidin-4-yl)-N-phenylpropionamide CAS RN®: 437-38-7.

1 DEFINITION

Fentanyl contains NLT 98.0% and NMT 102.0% of fentanyl (C₂₂H₂₈N₂O), calculated on the dried basis.

[Caution—Great care should be taken to prevent inhaling particles of Fentanyl and skin exposure.]

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

Solution A: Add 3 mL of triethylamine to about 950 mL of water in a 1000-mL volumetric ask. Adjust with perchloric acid to a pH of 2.62 ± 0.02, and dilute with water to volume.

Solution B: Acetonitrile

Diluent: Solution A and Solution B (9:1)

Mobile phase: See Table 1.

Table 1

System suitability stock solution: 0.1 mg/mL of USP Fentanyl Related Compound E RS prepared as follows. Transfer a suitable amount of USP Fentanyl Related Compound E RS to an adequate volumetric ask and dissolve in 50% of the nal volume using acetonitrile. Dilute with water to volume.

Standard stock solution: 1 mg/mL of USP Fentanyl RS prepared by dissolving in a suitable volumetric ask 40% lled with acetonitrile and diluting with water to volume

Standard solution: 0.1 mg/mL of USP Fentanyl RS from the Standard stock solution in Diluent

System suitability solution: 0.3 µg/mL of USP Fentanyl Related Compound E RS and 0.1 mg/mL of USP Fentanyl RS prepared by diluting System suitability stock solution and Standard stock solution with Diluent

Sample stock solution: 1 mg/mL of Fentanyl prepared as follows. Transfer a suitable amount of Fentanyl to an adequate volumetric ask. Add 25% of nal volume of acetonitrile, dissolve by shaking, and dilute with Diluent to volume.

Sample solution: 0.1 mg/mL of Fentanyl from the Sample stock solution in Diluent

3.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 206 nm

Column: 4.6-mm × 15-cm; 3.5-µm packing L7

Column temperature: 35°

Flow rate: 1 mL/min

Injection volume: 30 µL

3.2 System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 1.2 between fentanyl and fentanyl related compound E peaks, System suitability solution

Tailing factor: 0.5–2.0, Standard solution

Relative standard deviation: NMT 0.73%, Standard solution

3.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of fentanyl (C₂₂H₂₈N₂O) in the portion of Fentanyl taken:

Result = (r_U /r_S ) × (C_S /C_U ) × 100

r_U = peak response of fentanyl from the Sample solution

r_S = peak response of fentanyl from the Standard solution

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

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

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

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.5%

Organic Impurities

[Note—The use of high-purity (such as HPLC-grade) ammonium formate and ultratrace ammonium hydroxide is recommended.] Solution A: Acetonitrile and 10 mM ammonium formate (5:95). Adjust with ammonium hydroxide to a pH of 9.5.

Solution B: Acetonitrile and 10 mM ammonium formate (95:5). Adjust with ammonium hydroxide to a pH of 9.5.

Mobile phase: See Table 2.

Table 2

Diluent: 0.025% triuoroacetic acid in a mixture of acetonitrile and water (5:95)

Sensitivity solution: 0.5 µg/mL of USP Fentanyl RS prepared as follows. Transfer a suitable amount of USP Fentanyl RS to an adequate volumetric ask. Dissolve in 10% of nal volume using acetonitrile. Sonicate to dissolve, if necessary. Dilute with Diluent to volume. Standard solution: 2.0 µg/mL each of USP Fentanyl Related Compound E RS and USP Fentanyl Related Compound G RS prepared as follows. Transfer suitable amounts of USP Fentanyl Related Compound E RS and USP Fentanyl Related Compound G RS to an adequate volumetric ask. Dissolve in 10% of nal volume using acetonitrile. Sonicate to dissolve, if necessary. Dilute with Diluent to volume. Sample solution: 1.0 mg/mL of Fentanyl prepared as follows. Transfer a suitable amount of Fentanyl to an adequate volumetric ask. Dissolve in 10% of nal volume using acetonitrile. Sonicate to dissolve, if necessary. Dilute with Diluent to volume.

4.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 240 nm

Column: 4.6-mm × 15-cm; 3.5-µm packing L1

Column temperature: 45° Flow rate: 1.0 mL/min Injection volume: 40 µL

4.2 System suitability

Samples: Sensitivity solution and Standard solution

Suitability requirements

Relative standard deviation: NMT 5.0%, Standard solution

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

4.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of fentanyl related compound E in the portion of Fentanyl taken:

Result = (r_U /r_S ) × (C_S /C_U ) × 100

r_U = peak response of fentanyl related compound E from the Sample solution

r_S = peak response of fentanyl related compound E from the Standard solution

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

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

Calculate the percentage of each other impurity in the portion of Fentanyl taken:

Result = (r_U /r_S ) × (C_S /C_U) × (1/F) × 100

r_U = peak response of each other impurity from the Sample solution

r_S = peak response of fentanyl related compound G from the Standard solution

C_S = concentration of USP Fentanyl Related Compound G RS in the Standard solution (mg/mL)

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

F = relative response factor (see Table 3)

Acceptance criteria: See Table 3. The reporting threshold is 0.05%.

Table 3

^a The relative response factor is calculated against fentanyl related compound G.

^b 1-Phenethyl-4-(N-phenylpropionamido)piperidine 1-oxide.

^c 2-Oxo-N-(1-phenethylpiperidin-4-yl)-N-phenylpropanamide.

^d N-(1-Phenethylpiperidin-4-yl)-N-phenylbutyramide.

5 SPECIFIC TESTS

Loss on Drying 〈731〉

Analysis: Dry under vacuum at 60° for 2 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tightly closed, light-resistant containers. Store at 25°, excursions permitted between 15° and 30°.

USP Reference Standards 〈11〉

USP Fentanyl RS

USP Fentanyl Related Compound E RS

1-Phenethyl-N-phenylpiperidin-4-amine.

C₁₉H₂₄N₂    280.41

USP Fentanyl Related Compound G RS

N-(1-Phenethylpiperidin-4-yl)-N-phenylacetamide.

C₂₁H₂₆N₂O    322.44