Salmeterol Xinafoate

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

Salmeterol Xinafoate contains NLT 98.0% and NMT 102.0% of salmeterol xinafoate (C₂₅H₃₇NO₄ · C₁₁H₈O₃), calculated on the water- and solvent-free basis.

2 IDENTIFICATION

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

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

3 ASSAY

Procedure

[Note—It is recommended that solutions containing salmeterol be protected from light.]

Buffer A: 0.1 M sodium dodecyl sulfate

Buffer B: 0.1 M ammonium acetate

Mobile phase:

Acetonitrile, Buffer A, and Buffer B (52:24:24).

Adjust with glacial acetic acid to a pH of 3.8.

[Note—This may need as much as 75 mL of glacial acetic acid for each liter.]

System suitability solution:

0.25 mg/mL of USP Salmeterol Xinafoate RS and

0.02 mg/mL of USP Salmeterol Related Compound B RS in Mobile phase

Standard solution:

0.25 mg/mL of USP Salmeterol Xinafoate RS in Mobile phase

Sample solution:

0.25 mg/mL of Salmeterol Xinafoate in Mobile phase

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 278 nm

Column: 4.6-mm × 15-cm; 5-µm packing L1

Flow rate: 2 mL/min

Injection volume: 20 µL

System suitability

Sample: System suitability solution

[Note—The relative retention times for salmeterol related compound B and salmeterol are about 0.9 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 1.0 between salmeterol and salmeterol related compound B

Relative standard deviation: NMT 1.0% for salmeterol

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of salmeterol xinafoate (C₂₅H₃₇NO₄ · C₁₁H₈O₃) in the portion of Salmeterol Xinafoate taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

rᵤ = peak response from the Sample solution

rₛ = peak response from the Standard solution

Cₛ = concentration of USP Salmeterol Xinafoate RS in the Standard solution (mg/mL)

Cᵤ = concentration of Salmeterol Xinafoate in the Sample solution (mg/mL)

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

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.1%

Organic Impurities

[Note—It is recommended that solutions containing salmeterol be protected from light.]

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

Diluent: Acetonitrile and water (50:50)

Solution A: Acetonitrile, Buffer A, and Buffer B (52:24:24), pH 3.8 (adjusted with glacial acetic acid)

Solution B: Acetonitrile

Mobile phase: See Table 1.

System suitability solution:

5.0 mg/mL of USP Salmeterol Xinafoate RS and

0.3 mg/mL each of USP Salmeterol Related Compound A RS and USP Salmeterol Related Compound B RS in Diluent

Sample solution:

5.0 mg/mL of Salmeterol Xinafoate in Diluent

System suitability

Sample: System suitability solution

[Note—See Table 2 for relative retention times.]

Suitability requirements

Resolution: NLT 1.0 between salmeterol and salmeterol related compound B

Tailing factor: NMT 2.5 for salmeterol

Analysis

[Note—Disregard the peak due to hydroxynaphthoic acid and any peaks from blank injections.]

Sample: Sample solution

Calculate the percentage of any individual impurity in the portion of Salmeterol Xinafoate taken:

Result = (rᵢ / rₜ) × 100

rᵢ = peak response of each impurity from the Sample solution

rₜ = sum of all the peak responses from the Sample solution

a 1-Hydroxy-naphthalene-2-carboxylic acid. This is the counter ion of salmeterol and is included for identification only.

b 4-[1-Hydroxy-2-(6-phenethoxyhexylamino)ethyl]-2-(hydroxymethyl)phenol.

c 4-{1-Hydroxy-2-[6-(3-phenylpropoxy)hexylamino]ethyl}-2-(hydroxymethyl)phenol.

d 4-{1-Hydroxy-2-[4-{1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl}-2-(hydroxymethyl)phenoxy]ethyl}-2-(hydroxymethyl)phenol.

e 4-{1-Hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl}-2-methylphenol.

f 4-{1-Hydroxy-2-[(2-hydroxy-5-{1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl}benzyl)[6-(4-phenylbutoxy)hexyl]amino]ethyl}-2-(hydroxymethyl)phenol.

5 SPECIFIC TESTS

Water Determination 〈921〉, Method I

Sample: 0.5 g

Acceptance criteria: NMT 0.25%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage:

Preserve in tight containers. Store at a temperature not exceeding 30°.

USP Reference Standards 〈11〉

USP Salmeterol Xinafoate RS

USP Salmeterol Related Compound A RS

4-(1-Hydroxy-2-(4-phenylbutylamino)ethyl)-2-(hydroxymethyl)phenol.

C₁₉H₂₅NO₃ 315.41

USP Salmeterol Related Compound B RS

4-(1-Hydroxy-2-[6-(4-phenylbutan-2-yloxy)hexylamino]ethyl)-2-(hydroxymethyl)phenol.

C₂₅H₃₇NO₄ 415.57