Propofol Injectable Emulsion

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

Propofol Injectable Emulsion contains Propofol in a 10% (w/v) oil-in-water sterile emulsion. The aqueous component contains Glycerol, a suitable antimicrobial agent, and Water for Injection. It contains NLT 90.0% and NMT 110.0% of the labeled amount of propofol (C₁₂H₁₈O). It contains a suitable emulsifying agent.

2 IDENTIFICATION

Change to read:

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

▲[Note—Alternatively, the UV spectra of the major peak of the Sample solution and the Standard solution as obtained in the Assay may be used to meet the Acceptance criteria.]▲ (USP 1-Dec-2021)

Medium: Isopropyl alcohol

Standard solution: 100 µg/mL ▲of USP Propofol RS in Medium▲ (USP 1-Dec-2021)

Sample solution: ▲Nominally 100 µg/mL of propofol from Injectable Emulsion prepared as follows.▲ (USP 1-Dec-2021)

Dilute a volume of Injectable Emulsion, equivalent to 10 mg of propofol, with ▲Medium▲ (USP 1-Dec-2021) to 100 mL.

Wavelength range: 200–450 nm

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

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

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Procedure

Diluent: Dilute 68 mL of water with isopropyl alcohol to 1 L.

Mobile phase: Tetrahydrofuran and water (40:60)

Standard solution: 0.8 mg/mL of USP Propofol RS in Diluent

Sample solution: ▲Nominally 0.8 mg/mL of propofol prepared as follows.▲ (USP 1-Dec-2021)

Transfer a volume of well-shaken Injectable Emulsion, equivalent to about 40 mg of propofol, to a 50-mL volumetric flask. Dissolve in and dilute with isopropyl alcohol to volume, and mix.

▲ (USP 1-Dec-2021)

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 275 nm

▲[Note—For the alternative procedure in Identification A, use a diode array detector in the range of 200–400 nm.]▲ (USP 1-Dec-2021)

Column: 5-mm × 10-cm; 5-µm packing L1

Flow rate: 2 mL/min

Injection volume: 20 µL

System suitability

Sample: Standard solution

Suitability requirements

▲ (USP 1-Dec-2021)

Tailing factor: NMT 1.5

Relative standard deviation: NMT 2%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of propofol (C₁₂H₁₈O) in the portion of Injectable Emulsion taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

rᵤ = peak response ▲of propofol▲ (USP 1-Dec-2021) from the Sample solution

rₛ = peak response ▲of propofol▲ (USP 1-Dec-2021) from the Standard solution

Cₛ = concentration of USP Propofol RS in the Standard solution (mg/mL)

Cᵤ = nominal concentration of propofol in the Sample solution (mg/mL)

Acceptance criteria: 90.0%–110.0%

4 IMPURITIES

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Limit of Free Fatty Acids

[Note—To obtain a titer of sufficient sensitivity for the blank reagent, it is necessary to add stearic acid at a concentration of approximately 1.0 mmol/L. ▲For formulations containing known components that interfere with the quantitation of free fatty acids, the quantities of these components should be determined and subtracted from the final result.▲]

Titrimetric system

(See Titrimetry 〈541〉.)

Mode: Direct titration

Titrant: 0.05 M sodium hydroxide VS

Endpoint detection: Potentiometric▲ (USP 1-Dec-2021)

Blank titration: Weigh about 142.3 mg of stearic acid into a 500-mL volumetric flask. Dissolve in and dilute with dehydrated alcohol to volume to obtain the blank solution. Pipet 10 mL of the blank solution into a 100-mL beaker, and proceed as directed in the Analysis, beginning with “Add 0.5 mL of 0.05 N hydrochloric acid”.

Calculate the blank correction, B, in mmol/L:

Result = (N × Vᵦ / Vᵦₛ) − Nₛ

N = concentration of the Titrant (mmol/L)

Vᵦ = volume of the Titrant added between the first and second inflection points for the Blank titration (mL)

Vᵦₛ = volume of the blank solution used for the analysis (mL)

Nₛ = concentration of stearic acid (mmol/L)

Analysis

Sample: A volume of Injectable Emulsion, nominally equivalent to 100 mg of propofol

Transfer the Sample to a 100-mL beaker. Add 0.5 mL of 0.05 N hydrochloric acid, then dilute with a solution of alcohol and water (45:20) to 60 mL. Titrate with ▲Titrant▲ (USP 1-Dec-2021) to a potentiometric endpoint using a suitable electrode.

Calculate the free fatty acid content, in mmol/L:

Result = (N × Vᵤ / Vₛ) − B

N = concentration of the Titrant (mmol/L)

Vᵤ = volume of the Titrant added between the first and second inflection points (mL)

Vₛ = volume of Injectable Emulsion used for the analysis (mL)

B = blank correction factor (mmol/L), calculated as shown above

Acceptance criteria: NMT 7 mmol/L

Change to read:

Organic Impurities

Diluent, Mobile phase, and Sample solution: Proceed as directed in the Assay.

System suitability solution:

▲0.8 mg/mL of USP Propofol RS, 0.002 mg/mL of USP Propofol Related Compound A RS, and 0.0008 mg/mL of USP Propofol Related Compound B RS in Diluent▲ (USP 1-Dec-2021)

Standard solution:

0.002 mg/mL of USP Propofol Related Compound A RS and 0.0008 mg/mL of USP Propofol Related Compound B RS in Diluent

Chromatographic system: Proceed as directed in the Assay, except for the Detector.

Detector: 254 nm

System suitability

Sample: System suitability solution

[Note—The relative retention times for propofol related compound B, propofol, and propofol related compound A are about 0.8, 1.0, and 2.5, respectively.]

Suitability requirements

Resolution: NLT 2.5 between propofol and propofol related compound B

▲ (USP 1-Dec-2021)

Tailing factor: NMT 1.5 for the propofol peak

Relative standard deviation: NMT 2% for the propofol peak

Analysis

Samples: Sample solution and Standard solution

Calculate the percentage of propofol related compound A and propofol related compound B in the portion of Injectable Emulsion taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

rᵤ = peak response of propofol related compound A or propofol related compound B from the Sample solution

rₛ = peak response of propofol related compound A or propofol related compound B from the Standard solution

Cₛ = concentration of USP Propofol Related Compound A RS or USP Propofol Related Compound B RS in the Standard solution (mg/mL)

Cᵤ = nominal concentration of propofol in the Sample solution (mg/mL)

Acceptance criteria:

NMT 0.5% of propofol related compound A;

NMT 0.5% of propofol related compound B

5 SPECIFIC TESTS

Bacterial Endotoxins Test 〈85〉: It contains NMT 0.33 USP Endotoxin Units/mg of propofol.

Sterility Tests 〈71〉: Meets the requirements

pH 〈791〉: 4.5–8.5

Globule Size Distribution in Lipid Injectable Emulsions 〈729〉: Meets the requirements

Other Requirements: It meets the requirements in Injections and Implanted Drug Products 〈1〉.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve under an inert atmosphere of nitrogen. Store at controlled room temperature. Do not freeze.

Labeling: Label it to include the following:

Shake well before use.

Do not use if there is evidence of excessive creaming or aggregation, if large droplets are visible, or if there are other forms of phase separation indicating that the stability of the product has been compromised.

Slight creaming, which should disappear after shaking, may be visible upon prolonged standing.

Change to read:

USP Reference Standards 〈11〉

USP Propofol RS

USP Propofol Related Compound A RS

3,3′-5,5′-Tetraisopropyldiphenol;

▲Also known as 3,3′,5,5′-Tetraisopropylbiphenyl-4,4′-diol.

C₁₂H₁₈O₂ 354.53▲ (USP 1-Dec-2021)

USP Propofol Related Compound B RS

2,6-Diisopropyl-1,4-benzoquinone.

▲C₁₂H₁₆O₂ 192.26▲ (USP 1-Dec-2021)