Oxycodone Hydrochloride

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 · HCl 351.82

Morphinan-6-one, 4,5-epoxy-14-hydroxy-3-methoxy-17- methyl-, hydrochloride, (5α)-;

4,5α-Epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6- one hydrochloride CAS RN®: 124-90-3; UNII: C1ENJ2TE6C.

1 DEFINITION

Oxycodone hydrochloride contains NLT 97.0% and NMT 103.0% of oxycodone hydrochloride (C₁₈H₂₁NO₄ · HCl), calculated on the anhydrous, solvent-free basis.

2 IDENTIFICATION

Change to read:

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

Sample: Dissolve 250 mg of Oxycodone Hydrochloride in 25 mL of water. Render 25 mL of the resulting solution 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 at 105° for 2 h.

Acceptance criteria: Meets the requirements

B. The retention time of the oxycodone peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

3 ASSAY

Procedure

Mobile phase: 0.005 M sodium 1-hexanesulfonate, methanol, triethylamine, and phosphoric acid (900:100:2:5). Adjust with 50% sodium hydroxide solution to a pH of 2.5 ± 0.1 and filter.

System suitability solution: 13 µg/mL of USP Codeine Phosphate RS and 9 µg/mL of USP Oxycodone RS in Mobile phase Standard solution: 0.9 mg/mL of USP Oxycodone RS in Mobile phase

Sample solution: 1 mg/mL of Oxycodone Hydrochloride in Mobile phase. [Note—Pass a portion of this solution through a filter of 0.5-µm or finer pore size, and use the filtrate as the Sample solution.]

3.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 206 nm

Column: 3.9-mm × 15-cm; 4-µm packing L7

Column temperature: 50°

Flow rate: 1.5 mL/min

Injection volume: 10 µL

Run time: NLT 2 times the retention time of oxycodone

3.2 System suitability

Samples: System suitability solution and Standard solution

[Note—The relative retention times for codeine and oxycodone are about 0.8 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 3.0 between codeine and oxycodone, System suitability solution

Tailing factor: 0.75–1.25, Standard solution

Relative standard deviation: NMT 1.10%, Standard solution

3.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of oxycodone hydrochloride (C₁₈H₂₁NO₄ · HCl) in the portion of Oxycodone Hydrochloride taken: 

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

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

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

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

M_r1 = molecular weight of oxycodone hydrochloride, 351.82

M_r2 = molecular weight of oxycodone base, 315.37

Acceptance criteria: 97.0%–103.0% on the anhydrous, solvent-free basis

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.05%

[Note—Use of sulfuric acid is omitted.]

[Note—On the basis of the synthetic route, perform either Procedure 1 or Procedure 2. Procedure 1 is recommended if 8β-hydroxyoxycodone (7,8-dihydro-8β-14-dihydroxycodeinone) is a potential impurity.]

4.1 Organic Impurities, Procedure 1

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

Analysis

Sample: Sample solution

Calculate the percentage of each impurity in the portion of Oxycodone Hydrochloride taken:

Result = (r_U /r_T ) × 100

r_U = peak response of each impurity from the Sample solution

r_T = sum of the responses of all the peaks from the Sample solution

Acceptance criteria: See Table 1.

Table 1

a4,5α-Epoxy-3,14-dihydroxymorphinan-6-one.

b 4,5α-Epoxy-10α,14-dihydroxy-3-methoxy-17-methylmorphinan-6-one.

c 4,5α-Epoxy-3-methoxy-17-methylmorphinan-6α,14-diol.

d 4,5α-Epoxy-8β,14-dihydroxy-3-methoxy-17-methylmorphinan-6-one.

4.2 Organic Impurities, Procedure 2

Buffer: Mix 4.0 mL of heptafluorobutyric acid with 2000 mL of water and adjust with ammonium hydroxide to a pH of 2.3 ± 0.1.

Solution A: Methanol and Buffer (23:77)

Solution B: Methanol, tetrahydrofuran, and Buffer (20:3:77)

Mobile phase: See Table 2.

Table 2

Diluent: Trifluoroacetic acid and water (3:1000)

System suitability solution: 0.0067 mg/mL each of USP Hydrocodone RS and USP Oxycodone Related Compound A RS, and 3.0 mg/mL of USP Oxycodone Hydrochloride RS in Diluent

Standard solution: 0.0067 mg/mL of USP Hydrocodone RS in Diluent

Sample solution: 3.0 mg/mL of Oxycodone Hydrochloride in Diluent

4.2.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 280 nm

Column: 4.6-mm × 25-cm; 3-µm packing L1

Column temperature: 38°

Flow rate: 0.8 mL/min

Injection volume: 50 µL

4.2.2 System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 2.0 between oxycodone and hydrocodone; NLT 1.0 between hydrocodone and oxycodone related compound A, System suitability solution

Relative standard deviation: NMT 5.0%, Standard solution

4.2.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Oxycodone Hydrochloride taken:

Result = (r_U /r_S) × (C_S /C_U) × (M_r1 /M_r2) × (1/F) × 100

r_U = peak response of each impurity from the Sample solution

r_S = peak response of hydrocodone from the Standard solution

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

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

M_r1 = molecular weight of hydrocodone hydrochloride, 335.83

M_r2 = molecular weight of hydrocodone, 299.36

F = relative response factor (see Table 3)

Acceptance criteria: See Table 3. Disregard any peaks below 0.03%.

Table 3

a 4,5α-Epoxy-1,14-dihydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride.

b 4,5α-Epoxy-3-methoxy-17-methylmorphinan-6,14-diol hydrochloride.

c 4,5α-Epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-7-ene-6-one hydrochloride (oxycodone related compound A hydrochloride salt).

d 4,5α-Epoxy-14-hydroxy-3-methoxymorphinan-6-one hydrochloride.

5 SPECIFIC TESTS

Content of Chloride

Sample solution: 6 mg/mL of Oxycodone Hydrochloride in methanol

Analysis: To 50 mL of the Sample solution, add 5 mL of glacial acetic acid and titrate with 0.1 N silver nitrate VS, determining the endpoint potentiometrically. Each milliliter of 0.1 N silver nitrate is equivalent to 3.545 mg of chloride.

Acceptance criteria: 9.8%–10.4% on the anhydrous, solvent-free basis

Optical Rotation 〈781S〉, Procedures, Specific Rotation

Sample solution: 25 mg/mL of Oxycodone Hydrochloride in water on the anhydrous, solvent-free basis

Acceptance criteria: −137° to −149°

Water Determination 〈921〉, Method I: NMT 7.0%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers.

Labeling: The label states with which Organic Impurities procedure the article complies if Organic Impurities, Procedure 1 is not used.

USP Reference Standards 〈11〉

USP Codeine Phosphate RS

USP Hydrocodone RS

USP Oxycodone RS

USP Oxycodone Hydrochloride RS

USP Oxycodone Related Compound A RS

Also known as 14-Hydroxycodeinone;

4,5α-Epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-7-ene-6-one.

C₁₈H₁₉NO₄             313.35