Buprenorphine 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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1 DEFINITION

Buprenorphine Hydrochloride contains NLT 98.0% and NMT 102.0% of buprenorphine hydrochloride (C₂₉H₄₁NO₄·HCl), calculated on the anhydrous ▲and solvent-free▲ (USP 1-Aug-2022) basis.

2 IDENTIFICATION

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K ▲or 197A▲ (USP 1-Aug-2022)

B. The retention time of the buprenorphine 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 stock solution: 50 mg/mL of Buprenorphine Hydrochloride in methanol

Sample solution: 10 mg/mL of Buprenorphine Hydrochloride in carbon dioxide-free water from the Sample stock solution

Analysis: Use 3 mL of the Sample solution.

Acceptance criteria: Meets the requirements

3 ASSAY

Procedure

Buffer: 5.44 g/L of monobasic potassium phosphate prepared as follows. Initially dissolve in 90% volume of water, and adjust with 5% (v/v) phosphoric acid to a pH of 4.5. Dilute with water to volume.

Solution A: Acetonitrile and Buffer (10:90)

Solution B: Acetonitrile

Mobile phase: See Table 1. Return to the initial conditions and re-equilibrate the system.

Diluent: Methanol and water (80:20)

Standard solution: 2.0 mg/mL of USP Buprenorphine Hydrochloride RS in Diluent

Sample solution: 2.0 mg/mL of Buprenorphine Hydrochloride in Diluent

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 240 nm

Column: 4.6-mm × 10-cm; 3.5-µm packing L1

Column temperature: 30°

Flow rate: 1.3 mL/min

Injection volume: 5 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 buprenorphine hydrochloride (C₂₉H₄₁NO₄·HCl) in the portion of Buprenorphine Hydrochloride taken:

Result = (r₁/r₂) × (C₁/C₂) × 100

r₁ = peak response of buprenorphine from the Sample solution

r₂ = peak response of buprenorphine from the Standard solution

C₁ = concentration of USP Buprenorphine Hydrochloride RS in the Standard solution (mg/mL)

C₂ = concentration of Buprenorphine Hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: 98.0%–102.0% on the anhydrous ▲and solvent-free▲ (USP 1-Aug-2022) basis

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.1%

Organic Impurities

Buffer, Solution A, Solution B, and Mobile phase: Prepare as directed in the Assay.

System suitability solution: 5.0 mg/mL of USP Buprenorphine System Suitability Mixture RS in methanol

Sensitivity solution: 2.5 μg/mL of USP Buprenorphine Hydrochloride RS in methanol▲ (USP 1-Aug-2022)

Standard solution: 0.005 mg/mL of USP Buprenorphine Hydrochloride RS and 0.01 mg/mL of USP Buprenorphine Related Compound A RS in methanol

Sample solution: 5.0 mg/mL of Buprenorphine Hydrochloride in methanol

Chromatographic system: Proceed as directed in the Assay except for the Column.

Column: 4.6-mm × 5.0-cm; 3.5-µm packing L1

System suitability

Samples: System suitability solution, ▲Sensitivity solution,▲ (USP 1-Aug-2022) and Standard solution

Suitability requirements

Resolution: NLT 1.5 between buprenorphine and ethenobuprenorphine, System suitability solution

Relative standard deviation: NMT 5% for buprenorphine and buprenorphine related compound A, Standard solution

Signal-to-noise ratio: NLT 10, Sensitivity solution▲ (USP 1-Aug-2022)

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of buprenorphine related compound A in the portion of Buprenorphine Hydrochloride taken:

Result = (r₁/r₂) × (C₁/C₂) × 100

r₁ = peak response of buprenorphine related compound A from the Sample solution

r₂ = peak response of buprenorphine related compound A from the Standard solution

C₁ = concentration of USP Buprenorphine Related Compound A RS in the Standard solution (mg/mL)

C₂ = concentration of Buprenorphine Hydrochloride in the Sample solution (mg/mL)

Calculate the percentage of each other individual impurity in the portion of Buprenorphine Hydrochloride taken:

Result = (r₁/r₂) × (C₁/C₂) × (1/F) × 100

r₁ = peak response of each other individual impurity from the Sample solution

r₂ = peak response of buprenorphine from the Standard solution

C₁ = concentration of USP Buprenorphine Hydrochloride RS in the Standard solution (mg/mL)

C₂ = concentration of Buprenorphine Hydrochloride in the Sample solution (mg/mL)

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2. The reporting threshold is 0.05%.

a 2,2’-Bi{17-(cyclopropylmethyl)-4,5α-epoxy-3-hydroxy-7α-[(S)-2-hydroxy-3,3-dimethylbutan-2-yl]-6-methoxy-6α,14-ethanomorphinan}.

5 SPECIFIC TESTS

Optical Rotation 〈781S〉, Procedures, Specific Rotation

Sample solution: 20 mg/mL in methanol

Acceptance criteria: −92° to −98°, calculated on the anhydrous and solvent-free basis (USP 1-Aug-2022)

Acidity or Alkalinity

Sample stock solution: 50 mg/mL of Buprenorphine Hydrochloride in methanol

Sample solution: 10 mg/mL of Buprenorphine Hydrochloride in carbon dioxide-free water from Sample stock solution

Analysis: Add 0.05 mL of methyl red TS 2 to 10 mL of Sample solution and titrate with 0.02 N sodium hydroxide or 0.02 N hydrochloric acid.

Acceptance criteria: NMT 0.2 mL of 0.02 N sodium hydroxide or 0.02 N hydrochloric acid is required to change the color of the indicator

Water Determination 〈921〉, Method I: NMT 1.0%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight, light-resistant containers.

USP Reference Standards 〈11〉

USP Buprenorphine Hydrochloride RS

USP Buprenorphine Related Compound A RS

(S)-2-[17-(But-3-en-1-yl)-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethanomorphinan-7α-yl]-3,3-dimethylbutan-2-ol.

C₂₇H₃₃NO₄ 467.65

USP Buprenorphine System Suitability Mixture RS

Contains a mixture of the following two compounds:

Buprenorphine.

Ethenobuprenorphine (about 0.5%): (S)-2-[17-(Cyclopropylmethyl)-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethenomorphinan-7α-yl]-3,3-dimethylbutan-2-ol.

C₂₇H₃₃NO₄ 465.63