Propofol

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 contains NLT 98.0% and NMT 102.0% of propofol (C₁₂H₁₈O).

2 IDENTIFICATION

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197F

B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay, Procedure 1 or Procedure 2.

3 ASSAY

Procedure 1

[Note—This is to be performed in conjunction with Organic Impurities, Procedure 1.]

Internal standard solution: 10 mg/mL of USP 2,4,6-Tritertbutylphenol RS in methanol

Standard solution: 10 mg/mL of USP Propofol RS in Internal standard solution

Sample solution: 10 mg/mL of Propofol in Internal standard solution

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: GC

Detector: Flame ionization

Column: 0.53-mm × 30-m; coated with a 1.2-µm phase G16

Temperatures

Detector: 300°

Injection port: 250°

Column: See Table 1

Carrier gas: Helium

Flow rate: 8 mL/min

Injection volume: 1.0 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.5

Relative standard deviation: NMT 1.5% for the peak response ratio of propofol to the internal standard for five replicate injections

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of propofol (C₁₂H₁₈O) in the portion of Propofol taken:

Result = (Rᵤ / Rₛ) × (Cₛ / Cᵤ) × 100

Rᵤ = peak response ratio of propofol to the internal standard from the Sample solution

Rₛ = peak response ratio of propofol to the internal standard from the Standard solution

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

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

Acceptance criteria: 98.0%–102.0%

Change to read:

Procedure 2

[Note—This is to be performed in conjunction with Organic Impurities, Procedure 2.]

Mobile phase: Hexane, acetonitrile, and ▲alcohol, absolute▲ (ERR 1-Mar-2024) (990:7.5:1)

Standard solution: 2.4 mg/mL of USP Propofol RS in hexane

Sample solution: 2.4 mg/mL of Propofol in hexane

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 275 nm

Column: 4.6-mm × 20-cm; 5-µm packing L3

Flow rate: 2 mL/min

Injection volume: 10 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of propofol (C₁₂H₁₈O) in the portion of Propofol taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

rᵤ = peak response of propofol from the Sample solution

rₛ = peak response of propofol from the Standard solution

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

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

Acceptance criteria: 98.0%–102.0%

4 IMPURITIES

Organic Impurities, Procedure 1

[Note—On the basis of knowledge of the manufacturing process, either (1) Organic Impurities, Procedure 1 is performed in conjunction with Limit of Propofol Related Compound A, Limit of Propofol Related Compound B, Procedure 1, and Assay, Procedure 1; or (2) Organic Impurities, Procedure 2 is performed in conjunction with Limit of Propofol Related Compound B, Procedure 2 and the Assay, Procedure 2.]

System suitability solution: 100 mg/mL of USP Propofol Resolution Mixture RS in methanol

Standard solution: 0.1 mg/mL of USP Propofol RS in methanol

Sample solution: 100 mg/mL of Propofol in methanol

Chromatographic system: Proceed as directed in the Assay, Procedure 1.

System suitability

Samples: System suitability solution and Standard solution

[Note—See Table 2 for the relative retention times.]

Suitability requirements

Resolution: NLT 2 between propofol and 2-isopropyl-6-n-propylphenol, System suitability solution

Relative standard deviation: NMT 3.5% for six replicate injections, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Propofol taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

rᵤ = peak response for each impurity from the Sample solution

rₛ = peak response for propofol from the Standard solution

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

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

Acceptance criteria: See Table 2.

Table 2

Organic Impurities, Procedure 2

Mobile phase and Chromatographic system: Proceed as directed in the Assay, Procedure 2.

System suitability solution: 0.1 µL/mL of USP Propofol RS and 0.3 µL/mL of USP Propofol Related Compound B RS in hexane

Peak identification solution: 0.25 mg/mL of USP Propofol Related Compound A RS, 100 µL/mL of the Propofol that is under test, and 5 µL/mL of USP Propofol Related Compound C RS in hexane

Sample solution: 100 mg/mL of Propofol in hexane

Reference solution: 0.1 mg/mL of Propofol in hexane from the Sample solution

System suitability

Samples: System suitability solution and Peak identification solution

[Note—See Table 3 for the relative retention times.]

Suitability requirements

Resolution: NLT 4.0 between propofol related compound B and propofol, System suitability solution

Analysis

Samples: Sample solution and Reference solution

Calculate the percentage of each impurity in the portion of Propofol taken:

Result = (rᵤ / rₛ) × (1/F) × D × 100

rᵤ = peak response of each impurity from the Sample solution

rₛ = peak response of propofol from the Reference solution

F = relative response factor (see Table 3)

D = dilution factor used to prepare the Reference solution, 0.001

Acceptance criteria: See Table 3.

Table 3

Limit of Propofol Related Compound A

[Note—This test is to be performed in conjunction with Organic Impurities, Procedure 1.]

Mobile phase: Acetonitrile, methanol, and water (50:10:40)

Standard solution: 20 µg/mL of USP Propofol Related Compound A RS in methanol

Sample solution: 20 mg/mL of Propofol in methanol

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 270 nm

Column: 4.6-mm × 15-cm; packing L1

Flow rate: 1.5 mL/min

Injection volume: 20 µL

System suitability

Sample: Standard solution

Suitability requirements

Column efficiency: NLT 6000 theoretical plates

Relative standard deviation: NMT 15% for six replicate injections

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of propofol related compound A in the portion of Propofol taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

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

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

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

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

Acceptance criteria: NMT 0.1% of propofol related compound A

Limit of Propofol Related Compound B, Procedure 1

Sample: Propofol

Instrumental conditions

(See Ultraviolet-Visible Spectroscopy 〈857〉.)

Mode: UV

Analytical wavelength: 330 nm

Blank: Air

Analysis: Measure the absorbance of the Sample using air as the blank.

Acceptance criteria: NMT 0.1%; the absorbance of the Sample is NMT 0.4 absorbance units.

Limit of Propofol Related Compound B, Procedure 2

[Note—This is to be performed in conjunction with Organic Impurities, Procedure 2.]

Mobile phase: Prepare as directed in the Assay, Procedure 2.

Standard solution: 5 µg/mL of USP Propofol Related Compound B RS in hexane

Sample solution: 50 mg/mL of Propofol in hexane

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm × 20-cm; 5-µm packing L3

Flow rate: 2 mL/min

Injection volume: 20 µL

Analysis

Samples: Standard solution and Sample solution

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

Calculate the percentage of propofol related compound B in the portion of Propofol taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

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

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

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

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

Acceptance criteria: NMT 0.05% of propofol related compound B

5 SPECIFIC TESTS

Refractive Index 〈831〉: 1.5125–1.5145 at 20°

ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers under an atmosphere of inert gas, and protect from light. Store at controlled room temperature.

Labeling: The labeling indicates the Organic Impurities procedure with which the article complies if a procedure other than Organic Impurities, Procedure 1 is used.

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.

C₂₄H₃₄O₂ 354.53

USP Propofol Related Compound B RS

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

Also known as 2,6-Diisopropylcyclohexa-2,5-diene-1,4-dione.

C₁₂H₁₆O₂ 192.26

USP Propofol Related Compound C RS

2,6-Diisopropylphenyl isopropyl ether;

Also known as 2-Isopropoxy-1,3-diisopropylbenzene.

C₁₅H₂₄O 220.36

USP Propofol Resolution Mixture RS

Contains a mixture of the following two compounds:

Propofol.

2-Isopropyl-6-n-propylphenol.

USP 2,4,6-Tritertbutylphenol RS

2,4,6-Tri-tert-butylphenol.

C₁₈H₃₀O 262.44