Diethylene Glycol Monoethyl Ether

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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C₆H₁₄O₃                134.17

1 DEFINITION

Diethylene Glycol Monoethyl Ether contains NLT 99.0% and NMT 101.0% of C₆H₁₄O₃. It is produced by condensation of ethylene oxide and alcohol, followed by distillation.

2 IDENTIFICATION

Change to read:

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197F.(CN 1-May-2020) Potassium bromide plates being used

B. The retention time of the major peak of the Sample solution corresponds to that of the System suitability solution, as obtained in the Assay.

3 ASSAY

Procedure

Sample: Diethylene Glycol Monoethyl Ether (neat)

System suitability solution: 1 mg/mL each of 2- methoxyethanol, 2-ethoxyethanol, ethylene glycol, diethylene glycol, and USP Diethylene Glycol Monoethyl Ether RS in methanol

3.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: GC

Detector: Flame ionization

Column: 0.32-mm × 30-m fused-silica bonded with a 1.0-µm layer of phase G46

Temperature

Injector: 250°

Detector: 275°

Column: See the temperature program table below.

Carrier gas: Helium

Flow rate: 2.2 mL/min

Injection size: 0.5 µL

System suitability

Sample: System suitability solution

[Note—The relative retention times for 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, diethylene glycol monoethyl ether, and diethylene glycol are about 0.40, 0.43, 0.50, 0.93, and 1.0, respectively.]

3.2 Suitability requirements

Resolution: NLT 2.0 between 2-ethoxyethanol and ethylene glycol

Relative standard deviation: NMT 2.0%, determined from diethylene glycol monoethyl ether

3.3 Analysis

Sample: Diethylene Glycol Monoethyl Ether (neat)

Calculate the percentage of diethylene glycol monoethyl ether (C₆H₁₄O₃) in the portion of Diethylene Glycol Monoethyl Ether taken: 

Result = (r_U /r_T ) × 100

r_U = peak response for diethylene glycol monoethyl ether

r_T = sum of the responses of all the peaks

Acceptance criteria: 99.0%–101.0%

4 IMPURITIES

Organic Impurities

4.1 Procedure 1: Limit of Free Ethylene Oxide

Acetaldehyde solution: 10 µg/mL of acetaldehyde. [Note—Prepare fresh just before use.]

Ethylene oxide stock solution

[Caution—Ethylene oxide is toxic and ammable. Prepare these solutions in a well-ventilated fume hood, using great care. Protect both hands and face by wearing polyethylene protective gloves and an appropriate face mask.]

[Note—Before using the polyethylene glycol 200 in this test, remove any volatile components from it by placing 500 mL of the polyethylene glycol 200 in a 1000-mL round-bottom ask, attaching the ask to a rotary evaporator, and evaporating at a temperature of 60° at a pressure of 1.5–2.5 kPa for 6 h.]

Fill a chilled pressure bottle with liquid ethylene oxide, and store in a freezer when not in use. Use a small piece of polyethylene lm to protect the liquid from contact with the rubber gasket. Tare a glass-stoppered conical ask, add 50 mL of polyethylene glycol 200, and reweigh the ask. Transfer 5 mL of the liquid ethylene oxide to a 100-mL beaker chilled in a mixture of sodium chloride and wet ice (1:3). Using a gas-tight gas chromatographic syringe that has been previously cooled to −10°, transfer 300 µL (corresponding to about 250 mg) of liquid ethylene oxide to the polyethylene glycol 200, and swirl gently to mix. Replace the stopper, reweigh the ask, and determine the amount of ethylene oxide absorbed by weight difference. Adjust the weight of the mixture with polyethylene glycol 200 to 100.0 g, replace the stopper, and swirl gently to mix. This stock solution contains 2.5 mg/g of ethylene oxide. [Note—Prepare this Ethylene oxide stock solution fresh just before use, and store in a refrigerator.]

Ethylene oxide standard solution A: Tare a glass-stoppered conical ask, and chill it in a refrigerator. Add 35 mL of polyethylene glycol 200, and reweigh the ask. Use a gas-tight gas chromatographic syringe that has been chilled in a refrigerator, and transfer 1 g of the chilled Ethylene oxide stock solution to the tared, conical ask. Adjust the weight of the solution with polyethylene glycol 200 to 50.0 g, replace the stopper, and swirl gently to mix. Transfer 10 g of this solution to a 50-mL volumetric ask. Add 30 mL of water, and mix. Dilute with water to volume, and mix to obtain a solution containing 10 µg/mL of ethylene oxide. [Note—Prepare this solution fresh just before use, and store in a refrigerator.]

Ethylene oxide standard solution B: Transfer 10.0 mL of Ethylene oxide standard solution A to a 50-mL volumetric ask, and dilute with water to volume to obtain a solution containing 2 µg/mL of ethylene oxide. [Note—Prepare this solution fresh just before use, and store in a refrigerator.]

System suitability solution: Transfer 0.5 mL of Ethylene oxide standard solution B to a 10-mL pressure headspace vial, and add 0.1 mL of Acetaldehyde solution and 0.1 mL of water, seal the vial, and mix. Heat the mixture at 70° for 45 min.

Standard solution: Transfer 1 g of Diethylene Glycol Monoethyl Ether to a 10-mL pressure headspace vial, and add 0.5 mL of Ethylene oxide standard solution B and 0.5 mL of water. Seal the vial, and mix. Heat the mixture at 70° for 45 min.

Sample solution: Transfer 1 g of Diethylene Glycol Monoethyl Ether to a 10-mL pressure headspace vial, add 1 mL of water, seal the vial, and mix. Heat the mixture at 70° for 45 min.

4.1.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

[Note—The use of a headspace apparatus that automatically transfers a measured amount of headspace is allowed.] Mode: GC

Detector: Flame ionization

Column: 0.32-mm × 30-m glass or quartz capillary bonded with a 1.0-µm layer of phase G1

Temperature

Injector: 150°

Detector: 250°

Column: See the temperature program table below.

Carrier gas: Helium

Flow rate: 1 mL/min

Injection size: 1 mL

4.1.2 System suitability

Sample: Gaseous headspace of the System suitability solution

[Note—The relative retention times for acetaldehyde and ethylene oxide are about 0.94 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 2.0 between the acetaldehyde and ethylene oxide peaks

Relative standard deviation: NMT 15%

4.1.3 Analysis

Samples: Gaseous headspace of the Standard solution and Sample solution

[Note—Use a heated, gas-tight gas chromatographic syringe.]

Calculate the amount of ethylene oxide in the portion of Diethylene Glycol Monoethyl Ether taken:

Result = r_U/[(r_S × W_U ) − (r_U × W_S)]

r_U= ethylene oxide peak area from the Sample solution

r_S = ethylene oxide peak area from the Standard solution

W_U = weight of Diethylene Glycol Monoethyl Ether taken to prepare the Sample solution (g)

W_S = weight of Diethylene Glycol Monoethyl Ether taken to prepare the Standard solution (g)

Acceptance criteria: NMT 1 µg/g

4.2 Procedure 2: Limit of 2-Methoxyethanol, 2-Ethoxyethanol, Ethylene Glycol, and Diethylene Glycol

Sample, System suitability solution, Chromatographic system, and System suitability: Proceed as directed in the Assay.

Analysis: Proceed as directed in the Assay. 

Calculate the percentage of 2-methoxyethanol in the portion of Diethylene Glycol Monoethyl Ether taken: 

Result = (r_U /r_T ) × 100  

r_U = peak response for 2-methoxyethanol  

r_T = sum of all the peak responses 

Calculate the percentage of 2-ethoxyethanol in the portion of Diethylene Glycol Monoethyl Ether taken: 

Result = (r_U /r_T ) × 100 

r_U = peak response for 2-ethoxyethanol 

r_T = sum of all the peak responses 

Calculate the percentage of ethylene glycol in the portion of Diethylene Glycol Monoethyl Ether taken: 

Result = (r_U /r_T ) × 100 

r_U = peak response for ethylene glycol 

r_T = sum of all the peak responses 

Calculate the percentage of diethylene glycol in the portion of Diethylene Glycol Monoethyl Ether taken: 

Result = (r_U /r_T ) × 100 

r_U = peak response for diethylene glycol 

r_T = sum of all the peak responses 

Acceptance criteria: See Impurity Table 1.

Impurity Table 1

5 SPECIFIC TESTS

Refractive Index 〈831〉: 1.426–1.428 at 20°

Water Determination, Method I 〈921〉: NMT 0.1%, determined on a 10-g specimen

Fats and Fixed Oils, Acid Value〈401〉

[Note—This test must be performed promptly after sampling to avoid oxidation of the sample specimen.]

Analysis: Dissolve 30 g of Diethylene Glycol Monoethyl Ether in 30 mL of neutralized alcohol. Add 1 mL of phenolphthalein TS, and titrate with 0.01 N alcoholic potassium hydroxide VS to produce a permanent, faint pink color.

Acceptance criteria: The acid value so obtained is NMT 0.1.

Fats and Fixed Oils, Peroxide Value 〈401〉: NMT 8.0, 2 g being used

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers under an atmosphere of an inert gas, at a temperature not exceeding 35°. • Labeling: Label it to indicate that it is intended for topical or transdermal use only and it is stored under an atmosphere of an inert gas. The material is not to be used for parenterals.

USP Reference Standards 〈11〉

USP Diethylene Glycol Monoethyl Ether RS