Hydromorphone Hydrochloride Oral Solution

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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1 DEFINITION 

Hydromorphone Hydrochloride Oral Solution contains NLT 90.0% and NMT 110.0% of the labeled amount of hydromorphone hydrochloride (C₁₇H₁₉NO₃. HCl). It may contain suitable preservatives. 

2 IDENTIFICATION 

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

ASSAY 

Procedure 

Diluent: Phosphoric acid and water (1:1000) 

Solution A: 1.0 mg/mL of sodium 1-heptanesulfonate monohydrate in methanol and water (1:9). To each liter of this solution 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 methanol and water (1:1). To each liter of this solution 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 

The Standard solution and Sample solution should be kept in a cool place, protected from light. 

Standard solution: 0.08 mg/mL of USP Hydromorphone Hydrochloride RS in Diluent 

Sample solution: Nominally 0.08 mg/mL of hydromorphone hydrochloride obtained by diluting a suitable volume of Oral Solution in Diluent Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 220 nm 

Column: 4.6-mm × 5-cm; 3.5-µm packing L1 

Column temperature: 45° 

Flow rate: 1 mL/min 

Injection volume: 20 µL 

System suitability 

Sample: Standard solution 

Suitability requirements 

Tailing factor: NMT 1.5 for the hydromorphone peak 

Relative standard deviation: NMT 2.0% 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of the labeled amount of hydromorphone hydrochloride (C₁₇H₁₉NO₃. HCl) in the portion of Oral Solution taken:

Result = (r_U/r_S) × (C_S/C_U) × 100 

r_U = peak response from the Sample solution 

r_S = peak response from the Standard solution 

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

C_U = nominal concentration of hydromorphone hydrochloride in the Sample solution (mg/mL) 

Acceptance criteria: 90.0%–110.0% 

3 IMPURITIES 

Change to read: 

Organic Impurities 

Diluent, Solution A, and Solution B: Prepare as directed in the Assay. 

Mobile phase: See Table 2. 

Table 2 

The System suitability solution, Quantitation limit solution, Standard solution, and Sample solution should be kept in a cool place, protected from light. 

System suitability solution: 0.8 mg/mL of USP Hydromorphone Hydrochloride RS and 0.8 µg/mL of USP Hydromorphone Related Compound A RS in Diluent 

Quantitation limit solution: 0.4 µg/mL of USP Hydromorphone Hydrochloride RS in Diluent 

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

Sample solution: Nominally 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 mL/min 

Injection volume: 20 µL 

System suitability 

Samples: System suitability solution, Quantitation limit solution, and Standard solution 

Suitability requirements 

Resolution: NLT 1.0 between the hydromorphone related compound A and hydromorphone peaks, System suitability solution Signal-to-noise ratio: NLT 10:1, Quantitation limit solution 

Tailing factor: NMT 1.5 for the hydromorphone peak, 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 degradation product in the portion of Oral Solution taken: 

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

r_U = peak response for each degradation product found, including those in Table 3, 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 = nominal concentration of hydromorphone hydrochloride in the Sample solution (mg/mL) 

F = relative response factor for the corresponding individual species or unspecified impurity (see Table 3) 

Calculate the total degradation products by summing the percentage of all individual specified and unspecified degradation products determined to be at a level of 0.1% or greater, excluding the known process impurities, as indicated in Table 3. 

Acceptance criteria: See Table 3. Disregard peaks corresponding to those from the Diluent, peaks that elute before a relative retention time of about 0.50, except for any peak with a relative retention time of about 0.34, and peaks that elute at the relative retention times of the process-related substances designated in Table 3. 

Table 3 

^a Process impurity. 

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

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

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

^e Degradation product. 

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

^g(5α)-3-Hydroxy-2-[(5α)-3-hydroxy-17-methyl-6-oxo-4,5-epoxymorphinan-2-yl]-17-methyl-4,5-epoxymorphinan-6-one dihydrochloride.(ERR 1-Feb-2021) 

4 SPECIFIC TESTS 

Microbial Enumeration Tests 〈61〉 and Tests for Specified Microorganisms 〈62〉: The total aerobic microbial count does not exceed 102 cfu/mL, and the total yeasts and molds count does not exceed 10 cfu/mL. It meets the requirements of the test for the absence of Escherichia coli. pH 〈791〉: 3.5–6.5 

5 ADDITIONAL REQUIREMENTS 

Packaging and Storage: Preserve in tight containers, protected from light. Store at 25°, excursions permitted between 15° and 30°. Labeling: Identify in the product labeling any preservative used in the Oral Solution. 

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 hydrochloride. 

C₁₇H₁₇NO₃ 319.78