Fentanyl Citrate

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 · C₆H₈O₇   528.60 _{(ERR 1-May-2021)}

Propanamide, N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1);

N-(1-Phenethyl-4-piperidyl)propionanilide citrate (1:1);

N-(1-Phenethylpiperidin-4-yl)-N-phenylpropionamide 2-hydroxy-1,2,3-propanetricarboxylate _{(USP 1-May-2021)} CAS RN®: 990-73-8; UNII: MUN5LYG46H.

1 DEFINITION

Fentanyl Citrate contains NLT 98.0% and NMT 102.0% of fentanyl citrate (C₂₂H₂₈N₂O · C₆H₈O₇), calculated on the dried basis. 

[Caution—Great care should be taken to prevent inhaling particles of Fentanyl Citrate and exposing the skin to it.]

2 IDENTIFICATION

Change to read:

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K or 197A _{(USP 1-May-2021)}

Delete the following:

B. Spectroscopic Identification Tests 〈197〉, Ultraviolet-Visible Spectroscopy: 197U

Medium: Dilute hydrochloric acid in methanol (1 in 10)

Standard solution: 500 µg/mL of USP Fentanyl Citrate RS in Medium

Sample solution: 500 µg/mL of Fentanyl Citrate in Medium

Acceptance criteria: Meets the requirements _{(USP 1-May-2021)}

Add the following:

B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution as obtained in the Assay. _{(USP 1-May-2021)}

3 ASSAY

Change to read:

Procedure

[Note—The use of high purity (such as HPLC-grade) ammonium formate and ultratrace ammonium hydroxide is recommended.] Buffer: Dissolve 2.52 g of ammonium formate with 4 L of water.

Solution A: Acetonitrile and Buffer (5:95). Adjust with ammonium hydroxide to a pH of 9.5.

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

Mobile phase: See Table 1.

Table 1

Diluent: Acetonitrile, water, and triuoroacetic acid (5: 95: 0.025)

Standard solution: 1.6 mg/mL of USP Fentanyl Citrate RS prepared as follows. Transfer a suitable quantity of USP Fentanyl Citrate RS to an adequate volumetric ask. Dissolve with 90% of the ask volume of Diluent, and dilute with acetonitrile to volume. Sonicate if necessary. Sample solution: 1.6 mg/mL of Fentanyl Citrate prepared as follows. Transfer a suitable quantity of Fentanyl Citrate to an adequate volumetric ask. Dissolve with 90% of the ask volume of Diluent, and dilute with acetonitrile to volume. Sonicate if necessary.

3.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 260 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

3.2 System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.5

Relative standard deviation: NMT 0.73%

3.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of fentanyl citrate (C₂₂H₂₈N₂O · C₆H₈O₇) in the portion of Fentanyl Citrate 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 Citrate RS in the Standard solution (mg/mL)

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

(USP 1-May-2021)

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

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.5%

Delete the following:

4.1 Ordinary Impurities 〈466〉

Standard solution: In a mixture of chloroform and methanol (80:20). Eliminate the 0.01 mg/mL solution, and add a 0.02 mg/mL solution. Sample solution: In a mixture of chloroform and methanol (80:20)

Analysis: Use a thin-layer chromatographic plate coated with chromatographic silica gel with a calcium sulfate binder. Eluant: Chloroform, methanol, and formic acid (85:10:5)

Visualization: 3

Acceptance criteria: Meets the requirements (USP 1-May-2021)

Change to read:

4.2 Organic Impurities

Buffer, Solution A, Solution B, Mobile phase, Diluent, and Sample solution: Prepare as directed in the Assay. Standard stock solution 1: 50 μg/mL of USP Fentanyl Related Compound E RS prepared as follows. Transfer a suitable quantity of USP Fentanyl Related Compound E RS to an adequate volumetric ask. Dissolve with 10% of the ask volume of acetonitrile. Sonicate if necessary. Dilute with Diluent to volume.

Standard stock solution 2: 50 μg/mL of USP Fentanyl Related Compound G RS prepared as follows. Transfer a suitable quantity of USP Fentanyl Related Compound G RS to an adequate volumetric ask. Dissolve with 10% of the ask volume of acetonitrile. Sonicate if necessary. Dilute with Diluent to volume.

Sensitivity solution: 0.5 μg/mL of USP Fentanyl Related Compound G RS prepared as follows. Dilute Standard stock solution 2 with Diluent. 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 volumes of Standard stock solution 1 and Standard stock solution 2 to an adequate volumetric ask. Dilute with Diluent to volume.

4.2.1 Chromatographic system

Proceed as directed in the Assay, except for the Detector.

Detector: UV 240 nm

4.2.2 System suitability

Samples: Sensitivity solution and Standard solution

Suitability requirements

Relative standard deviation: NMT 5.0% for fentanyl related compound E and fentanyl related compound G, Standard solution Signal-to-noise ratio: NLT 10, Sensitivity solution

4.2.3 Analysis

Samples: Standard solution and Sample solution

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

Result = (r_U /r_S ) × (C_S /C_U ) × (M_r1 /M_r2 ) × 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 Citrate in the Sample solution (mg/mL)

M_r1 = molecular weight of fentanyl citrate, 528.60 (ERR 1-May-2021)

M_r2 = molecular weight of fentanyl, 336.48 (ERR 1-May-2021)

Calculate the percentage of any other specied or unspecied impurity relative to fentanyl in the portion of Fentanyl Citrate taken:

Result = (r_U /r_S ) × (C_S /C_U ) × (M_r1 /M_r2 ) × (1/F) × 100

r_U = peak response of any other specied or unspecied 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 Citrate in the Sample solution (mg/mL)

M_r1 = molecular weight of fentanyl citrate, 528.60 (ERR 1-May-2021)

M_r2 = molecular weight of fentanyl, 336.48 (ERR 1-May-2021)

F = relative response factor (see Table 2)

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

Table 2

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

^b The (% w/w) is calculated relative to fentanyl.

^c This peak is due to the counter ion of citrate. It is for peak identification only.

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

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

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

(USP 1-May-2021)

5 SPECIFIC TESTS

Loss on Drying 〈731〉

Analysis: Dry in vacuum at 60° for 2 h. Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

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

USP Reference Standards 〈11〉

USP Fentanyl Citrate 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 _{(USP 1-May-2021)}