Hydromorphone 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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C₁₇H₁₉NO₃.HCl 321.80 

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

4,5α-Epoxy-3-hydroxy-17-methylmorphinan-6-one hydrochloride CAS RN®: 71-68-1; UNII: L960UP2KRW. 

1 DEFINITION 

Hydromorphone Hydrochloride contains NLT 98.0% and NMT 102.0% of hydromorphone hydrochloride (C₁₇H₁₉NO₃.HCl), calculated on the dried basis. 

2 IDENTIFICATION 

Change to read: 

Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197A or 197K

The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. C. Identification Tests General 〈191〉, Chemical Identification Tests, Chloride 

Sample solution: 1 in 20 

Acceptance criteria: Meets the requirements 

3 ASSAY 

Procedure 

Solution A: 1.0 mg/mL of sodium 1-heptanesulfonate monohydrate in 1000 mL of methanol and water (1:9). Add 1.0 mL of triethylamine and adjust with phosphoric acid to a pH of 2.5 ± 0.1. 

Solution B: 1.0 mg/mL of sodium 1-heptanesulfonate monohydrate in 1000 mL of methanol and water (1:1). Add 1.0 mL of triethylamine and adjust with phosphoric acid to a pH of 2.5 ± 0.1. 

Mobile phase: See Table 1. 

Table 1 

Diluent: Phosphoric acid and water (1:1000) 

Standard solution: 0.4 mg/mL of USP Hydromorphone Hydrochloride RS in Diluent 

Sample solution: 0.4 mg/mL of Hydromorphone Hydrochloride in Diluent 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 220 nm 

Column: 3.9-mm × 15-cm; 5-µm packing L1 

Column temperature: 45° 

Flow rate: 1.0 mL/min 

Injection volume: 20 µL 

System suitability 

Sample: Standard solution 

Suitability requirements 

Tailing factor: NMT 2.0 

Relative standard deviation: NMT 0.73% 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of hydromorphone hydrochloride (C₁₇H₁₉NO₃.HCl) in the portion of Hydromorphone Hydrochloride taken:

Result = (r_U/r_S) × (C_S/C_U) × 100 

r_U = peak response of hydromorphone from the Sample solution 

r_S = peak response of hydromorphone from the Standard solution 

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

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

Acceptance criteria: 98.0%–102.0% on the dried basis 

4 IMPURITIES 

Residue on Ignition 〈281〉: NMT 0.3% 

[Note—On the basis of the synthetic route, perform either Organic Impurities, Procedure 1 or Organic Impurities, Procedure 2. Organic Impurities, Procedure 2 is recommended when hydromorphone aldol dimer and 7,8′-bishydromorphone may be present.] Organic Impurities, Procedure 1 

Solution A, Solution B, Diluent, and Chromatographic system: Proceed as directed in the Assay. 

Mobile phase: See Table 2. 

Table 2 

System suitability solution: 0.8 mg/mL each of USP Hydromorphone Hydrochloride RS and USP Hydromorphone Related Compound A RS in Diluent. The solution should be kept in a cool place protected from light. 

Standard solution: 4 µg/mL of USP Hydromorphone Hydrochloride RS in Diluent 

Sample solution: 0.8 mg/mL of Hydromorphone Hydrochloride in Diluent 

System suitability 

Samples: System suitability solution and Standard solution 

Suitability requirements 

Resolution: NLT 1.0 between the hydromorphone related compound A and hydromorphone peaks, System suitability solution Tailing factor: NMT 1.5, Standard solution 

Relative standard deviation: NMT 5.0%, Standard solution 

Analysis 

Samples: Diluent, Standard solution, and Sample solution 

Calculate the percentage of any specified or unspecified impurity in the portion of Hydromorphone Hydrochloride taken: 

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

r_U = peak response of each individual specified or unspecified impurity from the Sample solution

r_S = peak response of hydromorphone from the Standard solution 

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

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

F = relative response factor (see Table 3) 

Acceptance criteria: See Table 3. Disregard peaks corresponding to those obtained from the Diluent. 

Table 3 

^a 4,5α-Epoxy-17-methylmorphinan-3,8-diol-6-one.

^b 4,5α-Epoxy-17-methylmorphinan-3,6α-diol. 

^c 7,8-Didehydro-4,5α-epoxy-17-methylmorphinan-3,6α-diol. 

^d 4,5α-Epoxy-3-hydroxy-17-methylmorphinan-6-one N-oxide. 

^e 7,8-Didehydro-4,5α-epoxy-3-hydroxy-17-methylmorphinan-6-one. 

^f 8,14-Dihydrooripavine and 6β-tetrahydrooripavine are process impurities from another process and are controlled only if present. g(5β)-3-Hydroxy-2-[(5α)-3-hydroxy-17-methyl-6-oxo-4,5-epoxymorphinan-2-yl]-17-methyl-4,5-epoxymorphinan-6-one. Organic Impurities, Procedure 2 

Diluent: Phosphoric acid and water (1:100) 

Solution A: Mix 3520 mL of water, 18.40 g of monobasic ammonium phosphate, and 4.32 g of sodium 1-octanesulfonate. Add 4.0 mL of triethylamine, adjust with phosphoric acid to a pH of 2.90, and add 480 mL of acetonitrile. 

Solution B: Acetonitrile and water (160:40) 

Mobile phase: See Table 4. 

Table 4 

System suitability solution: 0.15 mg/mL of USP Hydromorphone Hydrochloride RS and 0.1 mg/mL of USP Morphine Sulfate RS in Diluent.

The solution should be kept in a cool place protected from light. 

Standard solution: 15 µg/mL of USP Hydromorphone Hydrochloride RS in Diluent 

Sample solution: 3 mg/mL of Hydromorphone Hydrochloride in Diluent 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 280 nm 

Column: 3.9-mm × 15-cm; 5-µm packing L7 

Column temperature: 40° 

Flow rate: 1.5 mL/min 

Injection volume: 10 µL 

Run time: 30 min 

System suitability 

Samples: System suitability solution and Standard solution 

Suitability requirements 

Resolution: NLT 4.0 between the morphine and hydromorphone peaks, System suitability solution 

Tailing factor: NMT 1.5 for the hydromorphone peak, System suitability solution 

Relative standard deviation: NMT 5.0%, Standard solution 

Analysis 

Samples: Diluent, Standard solution, and Sample solution 

Calculate the percentage of any specified or unspecified impurity in the portion of Hydromorphone Hydrochloride taken: 

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

r_U = peak response of each individual specified or unspecified impurity from the Sample solution

r_S = peak response of hydromorphone from the Standard solution 

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

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

F = relative response factor (see Table 5) 

Acceptance criteria: See Table 5. Disregard peaks corresponding to those obtained from the Diluent. 

Table 5 

^a 4,5α-Epoxy-17-methylmorphinan-3,6α-diol. 

^b 7,8-Didehydro-4,5α-epoxy-17-methylmorphinan-3,6α-diol. 

^c(5β)-3-Hydroxy-2-[(5α)-3-hydroxy-17-methyl-6-oxo-4,5-epoxymorphinan-2-yl]-17-methyl-4,5-epoxymorphinan-6-one. d(5α)-7-[(5α)-3,6-Dihydroxy-17-methyl-4,5-^e poxymorphinan-6-yl]-3-hydroxy-17-methyl-4,5-epoxymorphinan-6-one. e(5α)-3-Hydroxy-8-[(5α)-3-hydroxy-17-methyl-6-oxo-4,5-epoxymorphinan-7-yl]-17-methyl-4,5-epoxymorphinan-6-one. 

5 SPECIFIC TESTS 

Optical Rotation 〈781S〉, Procedures, Specific Rotation 

Sample solution: 50 mg/mL 

Acceptance criteria: Between −136° and −139° 

Acidity 

Sample: 300 mg 

Analysis: Dissolve the Sample in 10 mL of water, add 1 drop of methyl red TS, and titrate with 0.020 N sodium hydroxide VS. Acceptance criteria: NMT 0.30 mL is required to produce a yellow color.

Loss on Drying 〈731〉 

Analysis: Dry at 105° for 2 h. 

Acceptance criteria: NMT 1.5% 

6 ADDITIONAL REQUIREMENTS 

Packaging and Storage: Preserve in tight, light-resistant containers. Store at 25°, excursions permitted between 15° and 30°. Labeling: The labeling states with which Organic Impurities procedure the article complies, if other than Procedure 1. USP Reference Standards 〈11〉 

USP Hydromorphone Hydrochloride RS 

USP Hydromorphone Related Compound A RS 

7,8-Didehydro-4,5α-epoxy-3-hydroxy-17-methylmorphinan-6-one perchlorate. 

C₁₇H₁₇NO₃.HClO₄ 383.78 

USP Morphine Sulfate RS