Propofol Injectable Emulsion
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.
IDENTIFICATION
• A. Ultraviolet Absorption 
197U
197U
Wavelength range:
200–450 nm
Sample solution:
Dilute a volume of Injectable Emulsion, equivalent to 10 mg of propofol, with isopropyl alcohol to 100 mL.
Standard solution:
100 µg/mL
Medium:
Isopropyl alcohol
• B.
The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.
ASSAY
• Procedure
Diluent:
Dilute 68 mL of water with isopropyl alcohol to 1 L.
Mobile phase:
Prepare a filtered and degassed mixture of tetrahydrofuran and water (4:6).
Standard solution:
0.8 mg/mL of USP Propofol RS in Diluent
Sample solution:
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. The solution contains about 0.8 mg of propofol/mL.
Chromatographic system
Mode:
LC
Detector:
UV 275 nm
Column:
5-mm × 10-cm; 5-µm packing L1
Flow rate:
2 mL/min
Injection size:
20 µL
System suitability
Sample:
Standard solution
Suitability requirements
Column efficiency:
NLT 1000 theoretical plates
Tailing factor:
NMT 1.5 for the propofol peak
Relative standard deviation:
NMT 2% for the replicate injections
Analysis
Samples:
Standard solution and Sample solution
Calculate the quantity, as a percentage of the label claim, of C12H18O in the portion of Injectable Emulsion taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response from the Sample solution |
| rS | = | = peak response 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%
IMPURITIES
Organic Impurities
• Procedure 1: 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. ]
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 under Analysis, beginning with “add 0.5 mL of 0.05 N hydrochloric acid”.
Calculate the the blank correction, B, in mMol/L:
Result = (NVTB/VB) 
NSA
NSA
| N | = | = concentration of the titrant (mMol/L) |
| VTB | = | = volume of the titrant added between the first and second inflection points for the blank titration (mL) |
| VB | = | = volume of the blank solution used for the analysis (mL) |
| NSA | = | = 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 0.05 M sodium hydroxide VS to a potentiometric endpoint, using a suitable electrode.
Calculate the free fatty acid content, in mMol/L:
Result = (NVT /VS) B
B| N | = | = concentration of the titrant (mMol/L) |
| VT | = | = 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 5 mMol/L
• Procedure 2
Mobile phase and Diluent:
Prepare as directed in the Assay.
Standard solution:
Dissolve quantities of USP Propofol RS, USP Propofol Related Compound A RS, and USP Propofol Related Compound B RS in Diluent to obtain a solution having concentrations of 0.8 mg/mL of propofol and 0.002 and 0.0008 mg/mL of propofol related compound A and propofol related compound B, respectively.
Sample solution:
Prepare as directed in the Assay.
Chromatographic system:
Proceed as directed in the Assay, except that detection is at 254 nm.
System suitability
Sample:
Standard 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
Column efficiency:
NLT 1000 theoretical plates based on the propofol peak
Tailing factor:
NMT 1.5 for propofol peak
Relative standard deviation:
NMT 2% for the replicate injections for the propofol peak
Analysis
Samples:
Standard solution and Sample solution
Calculate the content of propofol related compound A and propofol related compound B, as a percentage of the label content of propofol, in the portion of Injectable Emulsion taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response for propofol related compound A or propofol related compound B from the Sample solution |
| rS | = | = peak response for 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
SPECIFIC TESTS
• Bacterial Endotoxins Test 85:
It contains NMT 0.33 USP Endotoxin Unit/mg of propofol.
85:
It contains NMT 0.33 USP Endotoxin Unit/mg of propofol.
• Sterility Tests 71:
Meets the requirements
71:
Meets the requirements
• pH 791:
4.5–8.5
791:
4.5–8.5
• Globule Size Distribution in Lipid Injectable Emulsions 729:
Meets the requirements
729:
Meets the requirements
• Other Requirements:
It meets the requirements under Injections 1.
1.
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.
• USP Reference Standards 11
11
USP Endotoxin RS
USP Propofol RS 
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USP Propofol Related Compound A RS
3,3¢-5,5¢-Tetraisopropyldiphenol.
3,3¢-5,5¢-Tetraisopropyldiphenol.
USP Propofol Related Compound B RS
2,6-Diisopropylbenzoquinone.
2,6-Diisopropylbenzoquinone.
Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Mary S. Waddell
Scientific Liaison 1-301-816-8124 |
(SM42010) Monographs - Small Molecules 4 |
| 85 |
Radhakrishna S Tirumalai, Ph.D.
Principal Scientific Liaison 1-301-816-8339 |
(GCM2010) General Chapters - Microbiology |
| 71 |
Radhakrishna S Tirumalai, Ph.D.
Principal Scientific Liaison 1-301-816-8339 |
(GCM2010) General Chapters - Microbiology |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 4449
Pharmacopeial Forum: Volume No. 37(3)