Oxycodone Terephthalate

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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(C₁₈H₂₁NO₄)  · C₈H₆O₄       796.86

Morphinan-6-one, 4,5-epoxy-14-hydroxy-3-methoxy-17-methyl-, 1,4-benzenedicarboxylate (2:1 salt), (5α); 4,5α-Epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one 1,4-benzenedicarboxylate (2:1 salt) CAS RN®: 64336-55-6.

1 DEFINITION

Oxycodone Terephthalate contains NLT 97.0% and NMT 103.0% of oxycodone terephthalate (C₁₈H₂₁NO₄)  · C₈H₆O₄, calculated on the dried basis.

2 IDENTIFICATION

A. Melting Range or Temperature 〈741〉

Sample solution: Transfer 50 mL of the filtrate retained from the test for Content of Terephthalate Acid to a 125-mL conical flask. Render the solution alkaline with 6 N ammonium hydroxide. Allow the mixture to stand until a precipitate is formed. Filter, wash the precipitate with 50 mL of cold water, and dry for 2 h at 105°.

Acceptance criteria: The precipitate melts between 218° and 223°, but the range between the beginning and end of the melting does not exceed 2°.

Change to read:

B. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K (CN 1-May-2020)

Sample: Use a portion of the dried precipitate obtained in Identification test A.

Acceptance criteria: Meets the requirements

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C. Spectroscopic Identification Tests 〈197〉, Ultraviolet-Visible Spectroscopy: 197U (CN 1-May-2020)

Sample solution: 150 µg/mL in 0.1 N hydrochloric acid

Acceptance criteria: Exhibits a maxima at 280 nm

3 ASSAY

Procedure

Mobile phase: To 2.2 g of sodium 1-octanesulfonate in 740 mL of water add 260 mL of methanol, 10 mL of glacial acetic acid, and 0.1 mL of triethylamine. Mix, and adjust with 5 N sodium hydroxide to a pH of 6.5 ± 0.1. Pass through a filter of 0.5-µm or finer pore size. Diluent: 0.1 N hydrochloric acid

Internal standard solution: 0.1 mg/mL of ethylparaben prepared by dissolving in 2% of the ask volume of methanol and diluting with Diluent to volume

Standard stock solution: 0.75 mg/mL of USP Oxycodone RS in Diluent

Standard solution: 0.11 mg/mL of USP Oxycodone RS prepared as follows. Transfer 15.0 mL of Standard stock solution to a 100-mL volumetric flask, add 20.0 mL of Internal standard solution, and dilute with Diluent to volume.

Sample stock solution: 0.71 mg/mL of Oxycodone Terephthalate in Diluent. Filter, discarding the first 5 mL.

Sample solution: 0.14 mg/mL of Oxycodone Terephthalate prepared as follows. Transfer 10.0 mL of the Sample stock solution to a 50-mL volumetric flask, add 10.0 mL of Internal standard solution, and dilute with Diluent to volume.

3.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 280 nm

Column: 3.9-mm × 15-cm; packing L1

Column temperature: 50 ± 1.0°

Flow rate: 1 mL/min

Run time: Twice the retention time of the main oxycodone peak

Injection size: 30 µL

3.2 System suitability

Sample: Standard solution

Suitability requirements

Resolution: NLT 6 between oxycodone and ethylparaben

Column efficiency: NLT 1800 theoretical plates

Relative standard deviation: NMT 2.0%

3.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of oxycodone terephthalate (C₁₈H₂₁NO₄)  · C₈H₆O₄ in the portion of Oxycodone Terephthalate taken: 

Result = (R_U /R_S) × (C_S /C_U) × (M_r1 /M_r2) × 100

R_U = peak response ratio of oxycodone to ethylparaben from the Sample solution

R_S = peak response ratio of oxycodone to ethylparaben from the Standard solution

C_S = concentration of USP Oxycodone RS in the Standard solution (mg/mL)

C_U = concentration of oxycodone in the Sample solution (mg/mL)

M_r1 = one-half of the molecular weight of oxycodone terephthalate, 398.43

M_r2 = molecular weight of oxycodone, 315.37

Acceptance criteria: 97.0%–103.0% on the dried basis

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 1%

4.1 Organic Impurities

Solution A: 2.2 g of sodium 1-octanesulfonate in 850 mL of water. Add 150 mL of methanol, 20 mL of glacial acetic acid, and 1.0 mL of triethylamine. Pass through a filter of 0.5-µm or finer pore size.

Solution B: 2.2 g of sodium 1-octanesulfonate in 500 mL of water. Add 500 mL of methanol, 20 mL of glacial acetic acid, and 1.0 mL of triethylamine. Pass through a filter of 0.5-µm or finer pore size.

Mobile phase: See Table 1.

Table 1

Diluent: 0.1 N hydrochloric acid

Standard stock solution: 0.9 mg/mL of USP Oxycodone RS in Diluent

Standard solution: 0.09 mg/mL of USP Oxycodone RS from the Standard stock solution, prepared by adding to 20% of the ask volume of methanol, and diluting with Diluent to volume

System suitability stock solution: 0.05 mg/mL of 4-hydroxybenzoic acid isopropyl ester in methanol

System suitability solution: 0.01 mg/mL of 4-hydroxybenzoic acid isopropyl ester and 0.09 mg/mL of USP Oxycodone RS in Diluent from the System suitability stock solution and Standard stock solution, respectively

Sample solution: 11 mg/mL of Oxycodone Terephthalate in methanol prepared as follows. Transfer the required amount of sample to a suitable volumetric flask. Add 80% of the ask volume of methanol, and shake by mechanical means for about 20 min to dissolve. Dilute with methanol to volume.

4.2 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 280 nm

Column: 3.9-mm × 15-cm; packing L1

Column temperature: 45 ± 1°

Flow rate: 1.5 mL/min

Injection size: 25 µL

4.3 System suitability

Samples: Standard solution and System suitability solution

Suitability requirements

Resolution: NLT 8 between the oxycodone and 4-hydroxybenzoic acid isopropyl ester peaks, System suitability solution Relative standard deviation: NMT 5.0%, Standard solution

4.4 Analysis

Samples: Standard solution and Sample solution

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

Result = (r_U /r_S) × (C_S /C_U) × (M_r1 /M_r2) × 100

r_U = peak area of an individual impurity from the Sample solution

r_S = peak area of oxycodone from the Standard solution

C_S = concentration of USP Oxycodone RS in the Standard solution (mg/mL)

C_U = concentration of Oxycodone Terephthalate in the Sample solution (mg/mL)

M_r1 = one-half of the molecular weight of oxycodone terephthalate, 398.43

M_r2 = molecular weight of oxycodone, 315.37

[Note—If any impurity is found having a retention time of about 2 in relation to that of the oxycodone peak, divide its apparent percentage by 4.8.]

Acceptance criteria

Individual impurities: NMT 1.0%

Total impurities: NMT 2.0%

5 SPECIFIC TESTS

Content of Terephthalic Acid

Sample solution: Transfer 1 g into a 50-mL beaker. Add 25 mL of 0.2 N hydrochloric acid, and heat to boiling with continuous stirring. Cover the beaker with a watch glass, and allow to cool to room temperature. Pass the suspension through a tared, medium-porosity filtering crucible. Transfer any material remaining in the beaker to the crucible with the aid of small portions of cold 0.2 N hydrochloric acid. Wash the material in the crucible with several portions of cold 0.2 N hydrochloric acid. [Note—Reserve the combined filtrates for use in Identification test A.]

Analysis: Dry the material in the crucible at 105° for 1 h, allow to cool, and reweigh. The material in the crucible is terephthalic acid. Determine the weight of terephthalic acid, and calculate the percentage of terephthalic acid.

Acceptance criteria: Between 20.2% and 21.5% of terephthalic acid (C₈H₆O₄) in Oxycodone Terephthalate on the dried basis

Loss on Drying 〈731〉: Dry a sample at 105° for 4 h: it loses NMT 1.5% of its weight.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers.

USP Reference Standards 〈11〉

USP Oxycodone RS