Poloxamer
HO(C2H4O)a(C3H6O)b(C2H4O)aH
Oxirane, methyl-, polymer with oxirane;
-Hydro-
-hydroxypoly(oxyethylene)a-poly(oxypropylene)b-poly(oxyethylene)a block copolymer, in which a and b have the values shown in the following table:
Polyethylene-polypropylene glycol
[9003-11-6].
(pol ox' a mer).
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HO(C2H4O)a(C3H6O)b(C2H4O)aH
Oxirane, methyl-, polymer with oxirane;
-Hydro--hydroxypoly(oxyethylene)a-poly(oxypropylene)b-poly(oxyethylene)a block copolymer, in which a and b have the values shown in the following table:
| Poloxamer | a | b |
|---|---|---|
| 124 | 12 | 20 |
| 188 | 80 | 27 |
| 237 | 64 | 37 |
| 338 | 141 | 44 |
| 407 | 101 | 56 |
Polyethylene-polypropylene glycol
[9003-11-6].DEFINITION
Poloxamer is a synthetic block copolymer of ethylene oxide and propylene oxide. It is available in several types, conforming to the requirements shown in the following table.
| Poloxamer | Physical Form |
Average Molecular Weight |
Weight (% Oxyethylene) |
Unsaturation (mEq/g) |
|---|---|---|---|---|
| 124 | Liquid | 2090–2360 | 46.7 ± 1.9 | 0.020 ± 0.008 |
| 188 | Solid | 7680–9510 | 81.8 ± 1.9 | 0.026 ± 0.008 |
| 237 | Solid | 6840–8830 | 72.4 ± 1.9 | 0.034 ± 0.008 |
| 338 | Solid | 12,700– 17,400 |
83.1 ± 1.7 | 0.031 ± 0.008 |
| 407 | Solid | 9840– 14,600 |
73.2 ± 1.7 | 0.048 ± 0.017 |
It may contain a suitable antioxidant.
IDENTIFICATION
• A. Infrared Absorption 
197F
:
Use a thin film of melted specimen if it is a solid. Use USP Poloxamer Liquid RS for Poloxamer 124, and use USP Poloxamer Solid RS for Poloxamer 188, 237, 338, and 407. Because of the differences in the ratios of copolymer composition, the intensity of some absorption bands may vary.
197F:
Use a thin film of melted specimen if it is a solid. Use USP Poloxamer Liquid RS for Poloxamer 124, and use USP Poloxamer Solid RS for Poloxamer 188, 237, 338, and 407. Because of the differences in the ratios of copolymer composition, the intensity of some absorption bands may vary.
ASSAY
• Average Molecular Weight
Phthalic anhydride–pyridine solution:
Dissolve 144 g of phthalic anhydride in freshly opened or freshly distilled pyridine containing less than 0.1% of water, and dilute with pyridine to 1000 mL. Protect from light, and allow to stand overnight. To verify that the Phthalic anhydride–pyridine solution has adequate strength, pipet 10 mL into a 250-mL conical flask, add 25 mL of pyridine and 50 mL of water, and after 15 min add 0.5 mL of a solution of phenolphthalein in pyridine (1 in 100), then titrate with 0.5 N sodium hydroxide VS: it consumes between 37.6 and 40.0 mL of 0.5 N sodium hydroxide.
Analysis:
Weigh a suitable quantity, not exceeding 15 g, of Poloxamer, calculated by multiplying the average molecular weight by 0.004, into a glass-stoppered, 250-mL boiling flask. Carefully pipet 25 mL of Phthalic anhydride–pyridine solution into the flask, touching the tip of the drained pipet to the protrusion in the flask. Add a few glass beads, and swirl to dissolve the specimen. Pipet 25 mL of Phthalic anhydride–pyridine solution into a second, glass-stoppered, conical flask, add a few glass beads, and use as the reagent blank. (An additional 25-mL portion of pyridine may be added to both the test specimen and reagent blank, before refluxing, if necessary to ensure fluidity.) Heat both flasks, fitted with suitable reflux condensers, and allow to reflux for 1 h. Allow to cool, and pour two 10-mL portions of pyridine through each condenser. Remove the flasks from the condensers, add 10 mL of water to each, insert the stoppers, swirl, and allow to stand for 10 min. To each flask add 50.0 mL of 0.66 N sodium hydroxide and 0.5 mL of a solution (1 in 100) of phenolphthalein in pyridine. Titrate with 0.5 N sodium hydroxide VS to a light pink endpoint that persists for NLT 15 s.
Calculate the average molecular weight:
Result = 2000 × W/[(VB 
VS) × N]
VS) × N]| W | = | = weight of the sample taken (g) |
| VB | = | = volume of 0.5 N sodium hydroxide VS consumed by the blank (mL) |
| VS | = | = volume of 0.5 N sodium hydroxide VS consumed by the residual acid in the test solution (mL) |
| N | = | = actual normality of the 0.5 N sodium hydroxide VS |
Acceptance criteria:
See the table in the Definition.
• Weight Percent Oxyethylene
Solvent:
Use deuterated water or deuterochloroform.
NMR reference:
Use sodium 2,2-dimethyl-2-silapentane-5-sulfonate (for deuterated water) or tetramethylsilane (for deuterochloroform).
Sample solution:
Dissolve 0.1–0.2 g of Poloxamer in deuterated water containing 1% of sodium 2,2-dimethyl-2-silapentane-5-sulfonate to obtain 1 mL of solution, or, if the Poloxamer does not dissolve in water, use deuterochloroform containing 1% of tetramethylsilane as the solvent.
Instrumental conditions
Mode:
Nuclear magnetic spectrometry
Sample size:
0.5–1.0 mL of the Sample solution
Analysis:
= (A2/A1) 1
Sample:
Sample solution
Transfer the Sample solution to a standard 5-mm NMR spinning tube, and if deuterochloroform is the solvent, add 1 drop of deuterated water, and shake the tube. Scan the region at 0–5 ppm, and use the calculation formulas specified below. Record as A1 the average area of the doublet appearing at about 1.08 ppm, representing the methyl groups of the oxypropylene units, and record as A2 the average area of the composite band at a range of 3.2–3.8 ppm, due to the CH2O groups of both the oxyethylene and oxypropylene units and also the CHO groups of the oxypropylene units, with reference to the sodium 2,2-dimethyl-2-silapentane-5-sulfonate or tetramethylsilane singlet at 0 ppm.
Calculate the percentage of oxyethylene, by weight, in the Poloxamer taken:
= (A2/A1) 1| A2 | = | = average area of the composite band at a range of 3.2–3.8 ppm |
| A1 | = | = average area of the doublet appearing at about 1.08 ppm |
Result = 3300 × /(33 × + 58)
/(33 × + 58)
Acceptance criteria:
See the table in the Definition.
• Unsaturation
Solution A:
Place 50 g of mercuric acetate in a 1000-mL volumetric flask, and dissolve with 900 mL of methanol to which 0.5 mL of glacial acetic acid has been added. Dilute with methanol to volume, and mix. Discard the solution if it is yellow. If it is turbid, filter it. Discard it if it is still turbid. Use fresh reagents if it is necessary to repeat the preparation of the solution. Protect the solution from light by storing it in an amber bottle in the dark.
Sample:
15.0 g
Analysis:
Transfer the Sample to a 250-mL conical flask. Pipet 50 mL of Solution A into the flask, and mix on a magnetic stirrer until solution is complete. Allow to stand for 30 min with occasional swirling. Add 10 g of sodium bromide crystals, and stir on a magnetic stirrer for 2 min. Without delay, add 1 mL of phenolphthalein TS, and titrate the liberated acetic acid with 0.1 N methanolic potassium hydroxide VS. Perform a blank determination. Determine also the initial acidity as follows. Dissolve 15.0 g of Poloxamer in 75 mL of methanol that has been neutralized with methanolic potassium hydroxide to the phenolphthalein endpoint. Add 1 mL of phenolphthalein TS, and titrate with the same 0.1 N methanolic potassium hydroxide VS under a nitrogen sweep.
Calculate the unsaturation, in mEq/g:
Result = (VU VB – VA) × N/15
VB – VA) × N/15| VU | = | = volume of 0.1 N methanolic potassium hydroxide used for titrating the test specimen (mL) |
| VB | = | = volume of 0.1 N methanolic potassium hydroxide used for titrating the blank (mL) |
| VA | = | = volume of 0.1 N methanolic potassium hydroxide used for titrating the initial acidity (mL) |
| N | = | = normality of the titrant |
Acceptance criteria:
See the table in the Definition.
IMPURITIES
• Heavy Metals, Method I 231:
NMT 20 ppm
231:
NMT 20 ppm
• Limit of Free Ethylene Oxide, Propylene Oxide, and 1,4-Dioxane
Stripped poloxamer:
Place 500 g of Poloxamer 124 into a suitable 3-neck, round-bottom flask equipped with a stirrer, a thermometer, a vacuum outlet, and a heating mantle. Evacuate the flask carefully at room temperature to a pressure of less than 10 mm of mercury, applying the vacuum slowly to avoid excessive foaming due to entrapped gases. After any foaming has subsided, heat the flask to 80
and continue to apply vacuum for 2 h; then cool to room temperature. Shut off the vacuum pump, and introduce nitrogen to bring the flask pressure back to atmospheric pressure. Transfer the Stripped poloxamer to a suitable nitrogen-filled container.
and continue to apply vacuum for 2 h; then cool to room temperature. Shut off the vacuum pump, and introduce nitrogen to bring the flask pressure back to atmospheric pressure. Transfer the Stripped poloxamer to a suitable nitrogen-filled container.
Standard solution
[Caution—Ethylene oxide, propylene oxide, and 1,4-dioxane are toxic and flammable. Prepare these solutions in a well-ventilated fume hood.
]
To a tared vial that can be sealed add 50.0 g of Stripped poloxamer. Add 60 µL of 1,4-dioxane and 75 µL of propylene oxide from a chilled syringe. Add ethylene oxide, using the following special handling procedure. Ethylene oxide, which is a gas at room temperature, is usually stored in a lecture-type gas cylinder or a small, metal pressure-bomb. Chill the cylinder in a refrigerator before use. Transfer 5 mL of the liquid ethylene oxide to a 100-mL beaker chilled in wet ice. Using a gas-tight syringe that has been chilled in a refrigerator, transfer 15 µL of the liquid ethylene oxide to the mixture. Immediately seal the vial, and shake on a vortex mixer for at least 30 s. Transfer 0.20 g of this solution to a tared vial that can be sealed, and add Stripped poloxamer to obtain a Standard solution having a final weight of 50.0 g. Each g of this Standard solution contains 1 µg of ethylene oxide, 5 µg of propylene oxide, and 5 µg of 1,4-dioxane. Transfer 1.00 ± 0.01 g of this solution to a 22-mL pressure headspace vial, and add about 0.01 g of butylated hydroxytoluene. Seal with a silicone septum with or without a pressure-relief star spring and with a pressure-relief, aluminum, safety sealing-cap, and crimp the cap closed with a cap-sealing tool.
Sample solution:
Transfer 1.00 ± 0.01 g of Poloxamer to a 22-mL pressure headspace vial, and add 0.01 g of butylated hydroxytoluene. Seal, cap, and crimp as directed for the Standard solution.
Chromatographic system
Mode:
GC (equipped with a balanced-pressure automated headspace sampler)
Detector:
Flame ionization
Column:
0.32-mm × 50-m fused-silica capillary; 5-µm layer of stationary phase G27 coating
Temperature
Detector:
250
Injector:
250
Transfer line:
140
Column:
See Table 1.
Table 1
| Initial Temperature ( ) |
Temperature Ramp ( /min) |
Final Temperature ( ) |
Hold Time at Final Temperature (min) |
|---|---|---|---|
| 70 | — | 70 | 10 |
| 70 | 10 | 240 | 10 |
Carrier gas:
Helium
Flow rate:
1.6 mL/min
Injection size:
Separately place the vials containing the Standard solution and the Sample solution in the automated sampler, and start the sequence so that the vial is heated at a temperature of 110 for 30 min before a suitable portion of its headspace is injected into the chromatograph.
for 30 min before a suitable portion of its headspace is injected into the chromatograph.
Autosampler
Needle-withdrawal time:
0.3 min
Pressurization time:
1 min
Injection time:
0.08 min
Vial pressure:
22 psig with the vial vent off
System suitability
Sample:
Standard solution
[Note—The relative retention times for ethylene oxide, propylene oxide, and 1,4-dioxane are about 1.0, 1.3, and 3.8, respectively. ]
Suitability requirements
Resolution:
NLT 2.0 between ethylene oxide and propylene oxide
Relative standard deviation:
NMT 15%
Analysis
Samples:
Standard solution and Sample solution
Calculate the concentrations, in µg/g, of ethylene oxide, propylene oxide, and 1,4-dioxane in the portion of Poloxamer taken:
Result = (rU/rS) × C
| rU | = | = peak response from the Sample solution |
| rS | = | = peak response from the Standard solution |
| C | = | = concentration of ethylene oxide, propylene oxide, or 1,4-dioxane in the Standard solution (µg/g) |
Acceptance criteria
Ethylene oxide:
NMT 1 µg/g
Propylene oxide:
NMT 5 µg/g
1,4-Dioxane:
NMT 5 µg/g
SPECIFIC TESTS
• pH 791:
5.0–7.5, in a solution (1 in 40)
791:
5.0–7.5, in a solution (1 in 40)
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in tight containers. No storage requirements specified.
• Labeling:
Label it to state, as part of the official title, the Poloxamer number. Label it to indicate the name and quantity of any antioxidant.
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Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Robert H. Lafaver, M.S.
Scientific Liaison 1-301-816-8335 |
(EXC2010) Monographs - Excipients |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 1893
Pharmacopeial Forum: Volume No. 33(4) Page 714