Fentanyl Citrate and Ropivacaine Hydrochloride Compounded Injection - Definition, Identification, Assay - USP 2025

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

Fentanyl Citrate and Ropivacaine Hydrochloride Compounded Injection contains NLT 90.0% and NMT 110.0% of the labeled amount of fentanyl (C₂₂H₂₈N₂O) and ropivacaine hydrochloride (C₁₇H₂₆N₂O · HCl).

Prepare Fentanyl Citrate and Ropivacaine Hydrochloride Compounded Injection containing 2 μg/mL of fentanyl and 1 mg/mL of ropivacaine hydrochloride as follows (see Pharmaceutical Compounding—Nonsterile Preparations 〈795〉).

^a Fentanyl Citrate 50-μg/mL injection, Hospira, Lake Forest, IL.

^b Ropivacaine Hydrochloride 0.5% (5 mg/mL) injection, Fresenius Kabi, Lake Zurich, IL.

Aseptically withdraw and combine 4 mL of the Fentanyl Citrate injection (50 μg/mL) (equivalent to 200 μg of fentanyl) and 20 mL of Ropivacaine Hydrochloride injection (5 mg/mL) (equivalent to 100 mg of ropivacaine hydrochloride) into an appropriate sterile container. Bring the preparation to a nal volume of 100 mL with Sodium Chloride for Injection (0.9%). Pass through a sterile lter of 0.22-µm pore size. [Note—Do not use a cellulose ester lter membrane for sterilization due to potential for adsorption.]

2 ASSAY

2.1 Procedure

Solution A: Add 2.72 g of dibasic potassium phosphate to 800 mL of water. Adjust with phosphoric acid to a pH of 5.8. Add 200 mL of methanol and mix well.

Mobile phase: See Table 1.

Table 1

Standard solution: 2 μg/mL of fentanyl and 0.075 mg/mL of ropivacaine hydrochloride prepared from USP Fentanyl Citrate RS and USP Ropivacaine Hydrochloride RS in water

Ropivacaine hydrochloride sample solution: Transfer 0.75 mL of Injection into a 10-mL volumetric ask, and dilute with water to volume. Fentanyl sample solution: 2 μg/mL of fentanyl from Injection

2.1.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 4.6-mm × 10-cm; 2.6-µm packing L1

Column temperature: 40°

Flow rate: 0.8 mL/min

Injection volume: 20 µL

2.1.2 System suitability

Sample: Standard solution

[Note—The retention times for ropivacaine hydrochloride and fentanyl are about 14.4 and 24.6 min, respectively.]

Suitability requirements

Tailing factor: NMT 2.0 for both fentanyl and ropivacaine hydrochloride

Relative standard deviation: NMT 2.0% for both fentanyl and ropivacaine hydrochloride from replicate injections

2.1.3 Analysis

Samples: Standard solution, Ropivacaine hydrochloride sample solution, and Fentanyl sample solution

Calculate the percentage of the labeled amount of fentanyl (C₂₂H₂₈N₂O) and ropivacaine hydrochloride (C₁₇H₂₆N₂O · HCl) in the portion of Injection taken:

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

r_U = peak response of fentanyl or ropivacaine hydrochloride from the relevant Sample solution

r_S = peak response of fentanyl or ropivacaine hydrochloride from the Standard solution

C_S = concentration of fentanyl or ropivacaine hydrochloride in the Standard solution (μg/mL or mg/mL, respectively) S

C_U = nominal concentration of fentanyl or ropivacaine hydrochloride in the relevant Sample solution (μg/mL or mg/mL, respectively)

Acceptance criteria: 90.0%–110.0%

2.2 Enantiomeric Purity

Mobile phase: Add 0.418 g of monobasic sodium phosphate and 0.941 g of dibasic sodium phosphate to 465 mL of water. Adjust with sodium hydroxide to a pH of 7.2 and add 35 mL of isopropanol. Mix well.

System suitability solution: Dissolve suitable quantities of USP Ropivacaine Hydrochloride RS and USP Ropivacaine Related Compound B RS in water. Dilute quantitatively, and stepwise, with water to obtain a solution containing about 75 μg/mL and 0.75 μg/mL, respectively. Sample solution: Transfer 0.75 mL of Injection into a 10-mL volumetric ask, and dilute with water to volume.

2.2.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4-mm × 10-cm; packing L41

Column temperature: 25°

Flow rate: 1.0 mL/min

Injection volume: 20 µL

2.2.2 System suitability

Sample: System suitability solution

[Note—The relative retention times for ropivacaine related compound B and ropivacaine hydrochloride are about 0.75 and 1.0, respectively.] Suitability requirement

Resolution: NLT 1.5 between ropivacaine related compound B (R-enantiomer) and ropivacaine (S-enantiomer)

2.2.3 Analysis

Sample: Sample solution

Calculate the percentage of ropivacaine related compound B (R-enantiomer) in the portion of Injection taken:

Result = (r_U /r_T ) × 100

r_U = peak response of ropivacaine related compound B (R-enantiomer)

r_T = sum of the peak responses of ropivacaine (S-enantiomer) and ropivacaine related compound B (R-enantiomer)

Acceptance criteria: NMT 2.0%

3 SPECIFIC TESTS

Change to read:

pH 〈791〉: 4.0–6.0 _{(USP 1-May-2024)}

Sterility Tests 〈71〉, Test for Sterility of the Product to Be Examined, Membrane Filtration: Meets the requirements

Bacterial Endotoxins Test 〈85〉: NMT 50.0 USP Endotoxin Units/mg of fentanyl and NMT 2.5 USP Endotoxin Units/mg of ropivacaine hydrochloride

Particulate Matter in Injections 〈788〉: Meets the requirements

4 ADDITIONAL REQUIREMENTS

Packaging and Storage: Package in a light-resistant, single-dose container. Store at controlled room temperature or in a refrigerator.

Beyond-Use Date: In the absence of passing a sterility and endotoxin test, the beyond-use dates in Pharmaceutical Compounding—Sterile Preparations 〈797〉 apply. After successful completion of sterility and endotoxin testing, NMT 90 days after the date on which it was compounded when stored at controlled room temperature or in a refrigerator.

Labeling: Label it to indicate that it is for use in a single patient only, and to state the Beyond-Use Date.

USP Reference Standards 〈11〉

USP Fentanyl Citrate RS

USP Ropivacaine Hydrochloride RS

USP Ropivacaine Related Compound B RS