Methylnaltrexone Bromide

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

Methylnaltrexone Bromide contains NLT 98.0% and NMT 102.0% of methylnaltrexone bromide (C₁₆H₂₀BrNO₄), calculated on the anhydrous and solvent-free basis.

2 IDENTIFICATION

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

B. 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, Bromide: Meets the requirements of the silver nitrate precipitation test

3 ASSAY

Procedure

Protect solutions containing methylnaltrexone bromide from light.

Buffer: Dilute 3.0 mL of heptafluorobutyric acid with water to 1000 mL. Adjust with ammonium hydroxide to a pH of 2.4.

Solution A: Buffer and methanol (85:15)

Solution B: Buffer, methanol, and tetrahydrofuran (85:5:10)

Mobile phase: See Table 1. Return to original conditions and re-equilibrate the system for about 15 min.

Table 1

Diluent: Solution A

Standard solution: 3.0 mg/mL of USP Methylnaltrexone Bromide RS in Diluent

Sample solution: 3.0 mg/mL of Methylnaltrexone Bromide in Diluent

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: 50°

Flow rate: 1.0 mL/min

Injection volume: 50 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 methylnaltrexone bromide (C₁₆H₂₀BrNO₄) in the portion of Methylnaltrexone Bromide taken:

Result = (r₁ / r₂) × (C₁ / C₂) × 100

r₁ = peak response from the Sample solution

r₂ = peak response from the Standard solution

C₁ = concentration of USP Methylnaltrexone Bromide RS in the Standard solution (mg/mL)

C₂ = concentration of Methylnaltrexone Bromide in the Sample solution (mg/mL)

Acceptance criteria: 98.0%–102.0% on the anhydrous and solvent-free basis

4 IMPURITIES

 Residue on Ignition 〈281〉: NMT 0.1%

Organic Impurities

Protect solutions containing methylnaltrexone bromide from light.

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

System suitability solution: 3.0 mg/mL of USP Methylnaltrexone Bromide RS and 4.5 µg/mL of USP Naltrexone RS in Diluent

Sensitivity solution: 1.5 µg/mL of USP Methylnaltrexone Bromide RS in Diluent

Standard solution: 4.5 µg/mL of USP Methylnaltrexone Bromide RS in Diluent

System suitability

Samples: System suitability solution, Sensitivity solution, and Standard solution

Suitability requirements

Resolution: NLT 1.5 between methylnaltrexone bromide and naltrexone, System suitability solution

Relative standard deviation: NMT 5.0%, Standard solution

Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Samples: Sample solution and Standard solution

Calculate the percentage of each impurity in the portion of Methylnaltrexone Bromide taken:

Result = (r₁ / r₂) × (C₁ / C₂) × 100

r₁ = peak response of each impurity from the Sample solution

r₂ = peak response of methylnaltrexone from the Standard solution

C₁ = concentration of USP Methylnaltrexone Bromide RS in the Standard solution (mg/mL)

C₂ = concentration of Methylnaltrexone Bromide in the Sample solution (mg/mL)

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

Table 2

ᵃ (17S)-17-(Cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxy-17-methyl-6-oxomorphinanium bromide.

ᵇ (17RS)-17-(But-3-en-1-yl)-4,5α-epoxy-3,14-dihydroxy-17-methyl-6-oxomorphinanium bromide.

ᶜ 3-Acetyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-17-methyl-6-oxomorphinanium bromide.

ᵈ 17-(Cyclopropylmethyl)-4,5α-epoxy-14-hydroxy-6-oxomorphinan-3-yl acetate.

ᵉ (17RS)-17-(Cyclopropylmethyl)-4,5α-epoxy-14-hydroxy-17-methyl-3-methoxy-6-oxomorphinanium bromide.

Limit of Methylnaltrexone Related Compound A

Buffer: 1.1 g/L solution of 1-octanesulfonate sodium salt in water (5 mM). Adjust with phosphoric acid to a pH of 2.00 ± 0.05.

Solution A: Tetrahydrofuran and Buffer (50:950)

Solution B: Acetonitrile, tetrahydrofuran, and Buffer (600:50:350)

Mobile phase: See Table 3. Return to original conditions and re-equilibrate the system for about 8 min.

Table 3

Diluent: Acetonitrile, water, and phosphoric acid (100:900:1.2).

[Note—This is v:v:v ratio equivalent to (100:900:2, v:v:w).]

Peak identification solution: 5 mg/mL of USP Methylnaltrexone Peak Identification Mixture RS in Diluent

Standard solution: 0.5 µg/mL of USP Methylnaltrexone Bromide RS in Diluent

Sample solution: 5 mg/mL of Methylnaltrexone Bromide in Diluent

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 225 nm

Column: 3.0-mm × 15-cm; 3.5-µm packing L1

Column temperature: 15°

Flow rate: 0.4 mL/min

Injection volume: 20 µL

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 10.0%

Analysis

Samples: Peak identification solution, Standard solution, and Sample solution

Identify the peak due to methylnaltrexone related compound A from the Peak identification solution.

[Note—Typical relative retention times for methylnaltrexone and methylnaltrexone related compound A are 1.0 and 1.2, respectively.]

Calculate the amount, in ppm, of methylnaltrexone related compound A in the portion of Methylnaltrexone Bromide taken:

Result = (r₁ / r₂) × (C₁ / C₂) × (1 / F) × 1000

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

r₂ = peak response of methylnaltrexone from the Standard solution

C₁ = concentration of USP Methylnaltrexone Bromide RS in the Standard solution (µg/mL)

C₂ = concentration of Methylnaltrexone Bromide in the Sample solution (mg/mL)

F = relative response factor for methylnaltrexone related compound A, 1.3

Acceptance criteria: NMT 100 ppm

5 SPECIFIC TESTS

pH 〈791〉

Sample solution: 75 mg/mL in water

Acceptance criteria: 4.3–5.3

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

Optical Rotation 〈781S〉, Procedures, Specific Rotation

Sample solution: 10 mg/mL in water

Acceptance criteria: −160° to −166°

Microbial Enumeration Tests 〈61〉 and Tests for Specified Microorganisms 〈62〉:

The total aerobic microbial count is NMT 10³ cfu/g, and the total combined yeasts and molds count is NMT 10² cfu/g.

Bacterial Endotoxins Test 〈85〉:

The level of bacterial endotoxins is such that the requirement under the relevant dosage form monograph(s) in which Methylnaltrexone Bromide

is used can be met. Where the label states that Methylnaltrexone Bromide must be subjected to further processing during the preparation of

injectable dosage forms, the level of bacterial endotoxins is such that the requirement under the relevant dosage form monograph(s) in which

Methylnaltrexone Bromide is used can be met.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers and store at room temperature.

Labeling: Where it must be subjected to further processing during the preparation of injectable dosage forms to ensure acceptable levels of

bacterial endotoxins, Methylnaltrexone Bromide is so labeled. Where it is sterile, it is so labeled.

USP Reference Standards 〈11〉

USP Endotoxin RS

USP Methylnaltrexone Bromide RS

USP Methylnaltrexone Peak Identification Mixture RS

It contains Methylnaltrexone Bromide and a small amount of methylnaltrexone related compound A:

7,8-Didehydromethylnaltrexone bromide, or ABUK-Methylnaltrexone.

(17RS)-17-(Cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxy-17-methyl-6-oxomorphinan-7-enium bromide.

C₁₆H₁₈BrNO₄ 434.32

USP Naltrexone RS