NF 31 Official Monographs / Polyethylene 2139

System suitability of 0.3 mL/min. Before calibration or analysis, increase Sample: Standard solution the flow slowly over a 1-min period to 0.8 mL/min. [NOTE—See the relative retention times table below.] Continue to pump Mobile phase through the column at this flow rate for at least 1 h before the first Relative injection. Check the flow gravimetrically, and adjust it Retention if necessary. Reduce the flow rate to about 0.1 mL/ Name Time min when the system is not in use.] Injection size: 50 µL Dextrose (glucose) 0.7 System suitability Sorbitol 0.8 Sample: Standard solution An isomer of 1,6-anhydro-D-glucose Chromatograph five replicate injections of the Standard (D-anhydroglucose furanose form) 0.9 solution, allowing 15 min between injections, and 1,6-Anhydro-D-glucose (levoglucosan) record the retention times of the components of the (D-anhydroglucose pyranose form) 1.0 Standard solution. Insert the average retention time along with the Suitability requirements molecular weight of each component in the Standard Resolution: NLT 1.0 solution into the calibration table of the molecular Relative standard derivation: NMT 5.0% weight distribution software. Check the regression Analysis results for a cubic fit of the calibration points, and Samples: Standard solution and Sample solution obtain a correlation coefficient, R, for the line. Use the peak response of USP 1,6-Anhydro-D-glucose Suitability requirements RS in the Standard solution for calculation of the Retention time: The retention times for each percentage of the isomer of 1,6-anhydro-D-glucose in component determined on replicate injections agree the Sample solution. Calculate the percentage of each within ±2 s. monomer in the portion of Hydrogenated Resolution: Dextrose and stachyose are baseline Polydextrose taken: resolved from one another and from the 5800-MW pullulan standard. Result = (rU/rS) × (CS/CU) × 100 [NOTE—Prominent negative baseline valleys are usually observed between the peaks for the 5800-, 23,700-, rU = peak response for the respective monomer and 100,000-MW pullulan standards.] from the Sample solution Correlation coefficient R: NLT 0.9999 rS = peak response for the respective monomer Analysis from the Standard solution Samples: Standard solution and Sample solution CS = concentration of the respective standard Use the molecular weight distribution software of the monomer in the Standard solution (mg/mL) data reduction system to generate a molecular weight CU = concentration of Hydrogenated Polydextrose distribution plot of Hydrogenated Polydextrose. in the Sample solution (mg/mL) Acceptance criteria: No measurable peak above a Acceptance criteria: NMT 4.0% of 1,6-anhydro-D- molecular weight of 22,000 is found. glucose, NMT 5.75% for sorbitol and NMT 0.25% for • PH 〈791〉: 5.0–7.0, in a solution (1 in 10) dextrose • WATER DETERMINATION, Method I 〈921〉: NMT 4.0%. Use a [NOTE—In the case of 1,6-anhydro-D-glucose, the peak mixture of Hydranal Solvent and Hydranal Formamide areas for the pyranose and furanose forms are dry (2:1) as a solvent. Perform the titration at 50° in a combined.] jacketed beaker. SPECIFIC TESTS ADDITIONAL REQUIREMENTS • MOLECULAR WEIGHT LIMIT • PACKAGING AND STORAGE: Preserve in tight, light-resistant Mobile phase: Dissolve 35.0 g of sodium nitrate and containers. Store in a cool and dry place. 1.0 g of sodium azide in 100 mL of water. Dilute with • USP REFERENCE STANDARDS 〈11〉 water to 4 L. Pass through a filter of 0.45-µm or finer USP 1,6-Anhydro-D-glucose RS pore size, and degas by applying an aspirator vacuum USP Dextrose RS for 30 min. The resulting Mobile phase is 0.1 N sodium USP Polydextrose RS nitrate containing 0.025% sodium azide. USP Sorbitol RS Standard solution: Transfer 20 mg each of USP Dextrose RS, stachyose, and 5800-, 23,700-, and 100,000-molecular weight (MW) pullulan standards into a 10-mL volumetric flask. Dissolve in and dilute with Mobile phase to volume. Pass through a syringe filter of . 0.45-µm or finer pore size into a suitable autosampler Polyethylene Glycol vial, and seal. Sample solution: Transfer 50 mg of Hydrogenated Polydextrose into a 10-mL volumetric flask. Dissolve in and dilute with Mobile phase to volume. Pass through a syringe filter of 0.45-µm or finer pore size into a Poly(oxy-1,2-ethanediyl), α-hydro-ω-hydroxy-; suitable autosampler vial, and seal. Polyethylene glycol [25322-68-3]. Chromatographic system (See Chromatography 〈621〉, System Suitability.) DEFINITION Mode: LC Polyethylene Glycol is an addition polymer of ethylene oxide Detector: Refractive index set at a sensitivity of and water, represented: 4 × 10−6 refractive index units full scale and maintained H(OCH2CH2)nOH at a temperature of 35 ± 0.1° Column: 7.8-mm × 30-cm; packing L39 in which n represents the average number of oxyethylene Column temperature: 45° groups. The average molecular weight is NLT 95.0% and Flow rate: 0.8 mL/min NMT 105.0% of the labeled nominal value if the labeled [NOTE—After installation of a new column, pump nominal value is less than 1000; it is NLT 90.0% and Mobile phase through the column overnight at a rate NMT 110.0% of the labeled nominal value if the labeled 2140 Polyethylene / Official Monographs NF 31

nominal value is between 1000 and 7000; and it is NLT Accceptance criteria: NMT 0.1% 87.5% and NMT 112.5% of the labeled nominal value if • HEAVY METALS 〈231〉 the labeled nominal value is more than 7000. It may con- Test preparation: 4.0 g in 5.0 mL of 0.1 N hydrochloric tain a suitable antioxidant. acid. Dilute with water to 25 mL. Acceptance criteria: NMT 5 ppm ASSAY • LIMIT OF FREE ETHYLENE OXIDE AND 1,4-DIOXANE • AVERAGE MOLECULAR WEIGHT Stripped polyethylene glycol 400: Into a 5000-mL, Phthalic anhydride solution: Place 49.0 g of phthalic 3-neck, round-bottom flask equipped with a stirrer, a anhydride into an amber bottle, and dissolve in 300 mL gas dispersion tube, and a vacuum outlet, place 3000 g of pyridine from a freshly opened bottle or pyridine of Polyethylene Glycol 400. At room temperature, that has been freshly distilled over phthalic anhydride. evacuate the flask carefully to a pressure of less than Shake vigorously until completely dissolved. Add 7 g of 1 mm of mercury, applying the vacuum slowly while imidazole, swirl carefully to dissolve, and allow to stand observing for excessive foaming due to entrapped for 16 h before using. gases. After any foaming has subsided and while stirring Sample solution for liquid Polyethylene Glycols: continuously, sparge with nitrogen, allowing the Carefully introduce 25.0 mL of the Phthalic anhydride pressure to rise to 10 mm of mercury. Continue solution into a dry, heat-resistant pressure bottle. Add stripping for a minimum of 1 h. Completeness of the an amount of the specimen equivalent to its expected stripping procedure should be verified by making a average molecular weight divided by 160. Insert the headspace injection of the stripped polyethylene glycol stopper in the bottle, and wrap it securely in a cloth 400. [NOTE—The 10-mm value is a guideline. Deviations bag. from this value affect only the total time required to Sample solution for solid Polyethylene Glycols: Care- strip the Polyethylene Glycol 400.] fully introduce 25.0 mL of Phthalic anhydride solution Shut off the vacuum pump, and bring the flask into a dry, heat-resistant pressure bottle. Add an pressure back to atmospheric pressure while amount of the specimen equivalent to its expected mo- maintaining nitrogen sparging. Remove the gas lecular weight divided by 160; however, because of lim- dispersion tube with the gas still flowing, and then turn ited solubility, do not use more than 25 g. Add 25 mL off the gas flow. Transfer the Stripped polyethylene glycol of pyridine, from a freshly opened bottle or pyridine 400 to a suitable nitrogen-filled container. that has been freshly distilled over phthalic anhydride. Standard solution: Transfer 4.90 g of Stripped Swirl to dissolve, insert the stopper in the bottle, and polyethylene glycol 400 to a tared 22-mL pressure wrap it securely in a cloth bag. headspace vial that can be sealed. Add 48 µL of 1,4- Blank: 25.0 mL of Phthalic anhydride solution plus any dioxane, equivalent to 50 mg of 1,4-dioxane, from a additional pyridine added to the bottle syringe; seal; and cap the vial. Analysis: Immerse the bottle in a water bath main- [CAUTION—Ethylene oxide and 1,4-dioxane are toxic and tained at a temperature between 96° and 100°, to the flammable. Prepare these solutions in a well-ventilated same depth as that of the mixture in the bottle. Re- fume hood.] move the bottles from the bath after 5 min and, with- Using the special handling described in the following, out unwrapping, swirl for 30 s to homogenize. Heat in complete the preparation. Ethylene oxide is a gas at the water bath for 30 min (60 min for Polyethylene room temperature. It is usually stored in a lecture-type Glycols having molecular weights of 3000 or more), gas cylinder or small metal pressure bomb. Chill the then remove from the bath, and allow it to cool to cylinder in a refrigerator before use. Transfer 5 mL of room temperature. Uncap the bottle carefully to release the liquid ethylene oxide to a 100-mL beaker chilled in any pressure, remove from the bag, add 10 mL of wet ice. Using a gas-tight syringe that has been chilled water, and swirl thoroughly. Wait 2 min, add 0.5 mL of in a refrigerator, transfer 57 µL of the liquid ethylene a solution of phenolphthalein in pyridine (1 in 100), oxide, equivalent to 50 mg of ethylene oxide, to the and titrate with 0.5 N sodium hydroxide VS to the first mixture contained in the headspace vial, and mix. With pink color that persists for 15 s. Perform a blank the aid of a syringe, transfer 2 mL of this solution to a determination. 5-mL beaker. Transfer 1.0 mL of this solution to a Calculate the average molecular weight taken: 100-mL volumetric flask, and dilute with Stripped polyethylene glycol 400 to volume. Transfer 10 mL of this Result = (2000 × W)/[(VB – VS) × N] solution to a 100-mL volumetric flask, dilute with Stripped polyethylene glycol 400 to volume, and mix to W = weight of the Polyethylene Glycol taken for obtain a Standard solution having known concentrations the Sample solution (g) of 10 µg/g for both ethylene oxide and 1,4-dioxane. VB = volume of 0.5 N sodium hydroxide consumed Transfer 1.0 mL of the Standard solution to a 22-mL by the Blank (mL) pressure headspace vial, seal with a silicone septum VS = volume of 0.5 N sodium hydroxide consumed with or without a pressure relief star spring and a by the specimen (mL) pressure relief safety aluminum sealing cap, and crimp N = normality of the sodium hydroxide solution the cap closed with a cap-sealing tool. Acceptance criteria: See Table 1. System suitability solution: Transfer 4.90 g of Stripped polyethylene glycol 400 to a 22-mL pressure headspace Table 1 vial. Pipet 50 µL of acetaldehyde into the vial. Using the Label Claim special handling described in Standard solution, transfer (Nominal Value) Acceptance Criteria 50.0 µL of liquid ethylene oxide into the vial. Immediately seal the vial, and shake. Transfer 1.0 mL of <1000 95.0–105.0% this solution to a 100-mL volumetric flask, and dilute 1000–7000 90.0–110.0% with Stripped polyethylene glycol 400 to volume. Transfer >7000 87.5–112.5% 10.0 mL of this solution to a 100-mL volumetric flask, and dilute with Stripped polyethylene glycol 400 to IMPURITIES volume. Transfer 1.0 mL of this System suitability solution to a 22-mL pressure headspace vial, and seal, cap, and • RESIDUE ON IGNITION 〈281〉 Sample: 25 g crimp as directed for the Standard solution. Analysis: Proceed as directed, using a platinum dish Sample solution: Transfer 1.0 g of Polyethylene Glycol and moistening the residue with 2 mL of sulfuric acid. to a 22-mL pressure headspace vial, and seal, cap, and crimp as directed for the Standard solution. NF 31 Official Monographs / Polyethylene 2141

Chromatographic system Calculate the percentage of ethylene glycol in the (See Chromatography 〈621〉, System Suitability.) portion of Polyethylene Glycol taken: Mode: Headspace GC (balanced pressure automatic headspace sampler) Result = (rU1/rS1) × (CS1/CU) × 100 Detector: Flame ionization Column: 0.32-mm × 50-m fused-silica capillary rU1 = peak height of ethylene glycol from the column containing bonded phase G27 in a 5-µm film Sample solution thickness rS1 = peak height of ethylene glycol from the Temperature Standard solution Column: See Table 2. CS1 = concentration of ethylene glycol in the Standard solution (mg/mL) CU = concentration of Polyethylene Glycol in the Table 2 Sample solution (mg/mL) Hold Time at Calculate the percentage of diethylene glycol in the Initial Temperature Final Final portion of Polyethylene Glycol taken: Temperature Ramp Temperature Temperature (°) (°/min) (°) (min) Result = (rU2/rS2) × (CS2/CU) × 100 70 10 250 — rU2 = peak height of diethylene glycol from the Injector: 85° Sample solution Detector: 250° rS2 = peak height of diethylene glycol from the Flow rate: 2.9 mL/min Standard solution Carrier gas: Helium CS2 = concentration of diethylene glycol in the Injection size: 1.0 mL of headspace using a 2-mL gas Standard solution (mg/mL) syringe preheated in an oven at 90° CU = concentration of Polyethylene Glycol in the System suitability Sample solution (mg/mL) Sample: System suitability solution Acceptance criteria: NMT 0.25% of the sum of [NOTE—The relative retention times for acetaldehyde ethylene glycol and diethylene glycol is found. and ethylene oxide are about 0.9 and 1.0, • LIMIT OF ETHYLENE GLYCOL AND DIETHYLENE GLYCOL (for respectively.] Polyethylene Glycol having a nominal molecular weight Suitability requirements 450 or more but NMT 1000) Resolution: NLT 1.3 between the acetaldehyde peak Ceric ammonium nitrate solution: 6.25 g of ceric and the ethylene oxide peak ammonium nitrate in 100 mL of 0.25 N nitric acid. Use Analysis within 3 days. Samples: Standard solution and Sample solution Standard stock solution: 2.5 mg/mL of diethylene [NOTE—The relative retention times for ethylene oxide glycol in 1:1 freshly distilled acetonitrile:water and 1,4-dioxane are about 1.0 and 3.4, respectively.] Sample stock solution: Dissolve 50.0 g of Polyethylene Place the vials containing the Standard solution and the Glycol in 75 mL of diphenyl ether, previously warmed if Sample solution into the automated sampler, and heat necessary, just to melt the crystals, in a 250-mL the vials at a temperature of 80° for 30 min. [NOTE—A distilling flask. Slowly distill at a pressure of 1–2 mm of headspace apparatus that automatically transfers the mercury, into a receiver graduated to 100 mL in 1-mL measured amount of headspace may be used to subdivisions, until 25 mL of distillate has been collected. perform the injection.] Add 20.0 mL of water to the distillate, shake vigorously, Acceptance criteria: The peak areas for ethylene oxide and allow the layers to separate. Cool in an ice bath to and 1,4-dioxane of the Sample solution are not greater solidify the diphenyl ether and facilitate its removal. than those of the corresponding peaks of the Standard Filter the separated aqueous layer, wash the diphenyl solution corresponding to NMT 10 µg/g of ethylene ether with 5.0 mL of ice-cold water, pass the washings oxide and NMT 10 µg/g of 1,4-dioxane. through the filter, and collect the filtrate and washings • LIMIT OF ETHYLENE GLYCOL AND DIETHYLENE GLYCOL (for in a 25-mL volumetric flask. Warm to room Polyethylene Glycol having a nominal molecular weight temperature, and dilute with water to volume, if less than 450) necessary. Mix this solution with 25.0 mL of freshly Standard solution: 0.5 mg/mL each of ethylene glycol distilled acetonitrile in a glass-stoppered, 125-mL and of diethylene glycol in water conical flask. Sample solution: 400 mg/mL of Polyethylene Glycol in Standard solution: Add 10.0 mL of the Standard stock water solution to 15.0 mL of Ceric ammonium nitrate solution. Chromatographic system Within 2–5 min, determine the absorbance of the (See Chromatography 〈621〉, System Suitability.) Standard solution. Mode: GC Sample solution: Add 10.0 mL of the Sample stock Detector: Flame ionization solution to 15.0 mL of Ceric ammonium nitrate solution. Column: 3-mm × 1.5-m stainless steel; packing of Within 2–5 min, determine the absorbance of the 12% G13 on support S1NS Sample solution. Temperature Blank: Mixture of 15.0 mL of Ceric ammonium nitrate Column: 140° solution and 10.0 mL of 1:1 freshly distilled Injector port: 250° acetonitrile:water Detector: 280° Instrumental conditions Carrier gas: Nitrogen or another suitable inert gas (See Spectrophotometry and Light-Scattering 〈851〉.) Flow rate: 50 mL/min Mode: UV-Vis Injection size: 2.0 µL Cell: 1 cm Analysis Analytical wavelength: 450 nm Samples: Standard solution and Sample solution Analysis [NOTE—The elution order is ethylene glycol followed Samples: Standard solution and Sample solution by diethylene glycol.] Acceptance criteria: The absorbance of the Sample solution does not exceed that of the Standard solution, corresponding to NMT 0.25% of combined ethylene glycol and diethylene glycol. 2142 Polyethylene / Official Monographs NF 31

SPECIFIC TESTS with an equal amount of Polyethylene Glycol 3350. • PH 〈791〉 [NOTE—If 6%–25% of an aqueous solution is to be incor- Sample solution: 5.0 g of Polyethylene Glycol in porated in the Ointment, replace 50 g of the Polyethylene 100 mL of carbon dioxide-free water. Add 0.30 mL of Glycol 3350 with an equal amount of stearyl alcohol.] saturated potassium chloride solution. Acceptance criteria: 4.5–7.5 ADDITIONAL REQUIREMENTS • COMPLETENESS AND COLOR OF SOLUTION: A solution of 5 g • PACKAGING AND STORAGE: Package in well-closed of Polyethylene Glycol in 50 mL of water is colorless; it is containers. clear for liquid grades and NMT slightly hazy for solid grades. • VISCOSITY—CAPILLARY VISCOMETER METHODS 〈911〉: Determine its viscosity by using a capillary viscometer . giving a flow time of NLT 200 s and using a liquid bath Polyethylene Glycol Monomethyl Ether maintained at 98.9 ± 0.3° (210° F). The viscosity is within the limits specified in Table 3. For a Polyethylene Glycol not listed in the table, calculate the limits by interpolation. Poly(oxy-1,2-ethanediyl), α-methyl-ω-hydroxy-; Table 3 Methoxy polyethylene glycol [9004-74-4]. Nominal Nominal DEFINITION Average Viscosity Average Viscosity Polyethylene Glycol Monomethyl Ether is an addition poly- Molecular Range, Molecular Range, mer of ethylene oxide and methanol, represented as: Weight Centistokes Weight Centistokes 200 3.9–4.8 2400 49–65 CH3(OCH2CH2)nOH 300 5.4–6.4 2500 51–70 in which n represents the average number of oxyethylene 400 6.8–8.0 2600 54–74 groups. The average molecular weight is NLT 95.0% and 500 8.3–9.6 2700 57–78 NMT 105.0% of the labeled nominal value if the labeled 600 9.9–11.3 2800 60–83 nominal value is below 1000; it is NLT 90.0% and NMT 700 11.5–13.0 2900 64–88 110.0% of the labeled nominal value if the labeled nomi- 800 12.5–14.5 3000 67–93 nal value is between 1000 and 4750; and it is NLT 87.5% and NMT 112.5% of the labeled nominal value if the la- 900 15.0–17.0 3250 73–105 beled nominal value is above 4750. 1000 16.0–19.0 3350 76 –110 1100 18.0–22.0 3500 87–123 ASSAY 1200 20.0–24.5 3750 99–140 • AVERAGE MOLECULAR WEIGHT 1300 22.0–27.5 4000 110–158 Phthalic anhydride solution: Place 49.0 g of phthalic anhydride into an amber bottle, and dissolve in 300 mL 1400 24–30 4250 123–177 of pyridine, either from a freshly opened bottle or 1450 25–32 4500 140–200 freshly distilled over phthalic anhydride. Shake vigor- 1500 26–33 4750 155–228 ously until completely dissolved. Add 7 g of imidazole, 1600 28–36 5000 170–250 swirl carefully to dissolve, and allow to stand for 16 h 1700 31–39 5500 206–315 before using. 1800 33–42 6000 250–390 Sample solution for liquid Polyethylene Glycol Mono- methyl Ethers: Carefully introduce 25.0 mL of the 1900 35–45 6500 295–480 Phthalic anhydride solution into a dry, heat-resistant 2000 38–49 7000 350–590 pressure bottle. Add a weighed amount of the sample, 2100 40–53 7500 405–735 equivalent to its expected average molecular weight di- 2200 43–56 8000 470–900 vided by 80. Insert the stopper in the bottle, and wrap 2300 46–60 — — it securely in a cloth bag. Sample solution for solid Polyethylene Glycol Mono- methyl Ethers: Carefully introduce 25.0 mL of Phthalic ADDITIONAL REQUIREMENTS anhydride solution into a dry, heat-resistant pressure • PACKAGING AND STORAGE: Preserve in tight containers. bottle. Add an amount of the sample, equivalent to its • LABELING: Label it to state, as part of the official title, the expected molecular weight divided by 80; however, be- average nominal molecular weight of the Polyethylene cause of limited solubility, do not use more than 25 g. Glycol. Label it to indicate the name and quantity of any Add 25 mL of pyridine, either from a freshly opened added antioxidant. bottle or freshly distilled over phthalic anhydride, swirl to dissolve, insert the stopper in the bottle, and wrap it securely in a cloth bag. Analysis: Immerse the bottle in a water bath main- . tained at 96°–100° to the same depth as that of the Polyethylene Glycol Ointment mixture in the bottle. Remove the bottle from the bath after 5 min, and without unwrapping, swirl for 30 s to DEFINITION homogenize. Heat in the water bath for 30 min (60 Prepare Polyethylene Glycol Ointment as follows. min for Polyethylene Glycol Monomethyl Ethers having molecular weights of 3000 or higher), then remove Polyethylene Glycol 3350 400 g from the bath, and allow to cool to room temperature. Uncap the bottle carefully to release any pressure, re- Polyethylene Glycol 400 600 g move from the bag, add 10 mL of water, and swirl To make 1000 g thoroughly. Wait for 2 min, add 0.5 mL of a solution of phenolphthalein in pyridine (1 in 100). Titrate with 0.5 Heat the two ingredients on a water bath to 65°. Allow to N sodium hydroxide VS to the first pink color that per- cool, and stir until congealed. If a firmer preparation is sists for 15 s, recording the volume, in mL, of 0.5 N desired, replace up to 100 g of the Polyethylene Glycol 400