Salmeterol Inhalation Powder

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 Inhalation Powder for use in dry powder inhalers contains an amount of salmeterol xinafoate (C₂₅H₃₇NO₄ · C₁₁H₈O₃) equivalent to NLT 90% and NMT 110% of the labeled amount of salmeterol (C₂₅H₃₇NO₄).

2 IDENTIFICATION

Change to read:

A. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. (IRA 1-Sep-2022)

3 ASSAY

3.1 Procedure

Buffer: 0.15 M ammonium acetate

Mobile phase: Methanol, Buffer, and formic acid (65:35:0.5)

Diluent: Methanol and water (70:30)

System suitability solution: 11 µg/mL of USP Salmeterol Resolution Check RS in Diluent

Standard solution: 9 µg/mL of USP Salmeterol Xinafoate RS in Diluent

Sample solution: Nominally 6 µg/mL of salmeterol free base from NLT 12 unit doses in Diluent

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 276 nm

Column: 4.6-mm × 20-cm; 5-µm packing L1

Column temperature: 40°

Flow rate: 1.5 mL/min

Injection volume: 200 µL

System suitability

Sample: System suitability solution

[Note—The relative retention times for salmeterol and salmeterol-deoxy are 1.0 and 1.4, respectively.]

Suitability requirements

Resolution: NLT 2.0 between salmeterol and salmeterol-deoxy

Tailing factor: NMT 1.5 for the salmeterol peak

Relative standard deviation: NMT 2% for the salmeterol peak

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of salmeterol (C₂₅H₃₇NO₄) in the portion of the sample taken:

Result = (r_U/r_S) × (C_S/C_U) × (M_r1/M_r2) × 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

C_S = concentration of USP Salmeterol Xinafoate RS in the Standard solution (µg/mL)

C_U = nominal concentration of salmeterol free base in the Sample solution (µg/mL), based on the target emitted dose of 47 µg

M_r1 = molecular weight of salmeterol free base, 415.57

M_r2 = molecular weight of salmeterol xinafoate, 603.75

Acceptance criteria: 90%–110%

Delete the following:

4 PERFORMANCE TESTS (IRA 1-Sep-2022)

5 IMPURITIES

Change to read:

5.1 Organic Impurities

[Note—Protect the Sample solution and Standard solution from light.]

Diluent: Methanol and water (70:30)

Solution A: Trifluoroacetic acid in water (0.05%, v/v)

Solution B: Trifluoroacetic acid in acetonitrile (0.05%, v/v)

Mobile phase: See Table 1.

Table 1 (IRA 1-Sep-2022)

^a This time may be increased to ensure equilibration.

System suitability solution: 0.1 mg/mL of USP Salmeterol System Suitability RS in Diluent

Standard solution: 2.5 µg/mL of USP Salmeterol Related Compound H RS in Diluent

Sample solution: Nominally 50 µg/mL of salmeterol free base from NLT 10 unit doses prepared as follows. Weigh, and transfer the contents of the appropriate number of unit doses to a suitable volumetric flask. Add 80% of the flask volume of Diluent, and sonicate for 5 min. Cool to room temperature, and dilute with Diluent to volume. Allow the undissolved material to settle, and inject the supernatant.

Chromatographic system

Mode: LC

Detector: UV 215 nm

Column: 4.6-mm × 25-cm; 5-µm packing L1

Column temperature: 30°

Flow rate: 1.0 mL/min

Injection volume: 50 µL

System suitability:

Resolution: NLT 2 between salmeterol-N-alkyl and salmeterol related compound H

Relative standard deviation: NMT 2% for salmeterol related compound H

Analysis

Calculate the percentage of salmeterol related compound H in the portion of the sample taken:

Result = (r_U/r_S) × C_S × V × (W_N/W_U) × (1/L) × 100

r_U = peak response of each degradation product from the Sample solution

r_S = peak response of salmeterol related compound H from the Standard solution

C_S = concentration of USP Salmeterol Related Compound H RS in the Standard solution (µg/mL)

V = volume of the Sample solution (mL)

W_N = theoretical unit dose weight (mg/unit dose)

W_U = weight of Inhalation Powder in the Sample solution (mg)

L = label claim of salmeterol free base (µg/unit dose)

Acceptance criteria: See Table 2.

Table 2 (IRA 1-Sep-2022)

^a Included for identification purposes only. Process impurities controlled in the drug substance and not to be included in the total impurities.

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

^c 4-{1-Hydroxy-2-[6-(4-phenylbutan-2-yloxy)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.

^g Includes all degradation product peaks ≥0.05%.

6 SPECIFIC TESTS

Change to read:

Microbial Enumeration Tests 〈61〉 and Tests for Specified Microorganisms 〈62〉: It meets the requirements of the tests for absence of Staphylococcus aureus, Pseudomonas aeruginosa, and bile-tolerant Gram-negative bacteria in 1 g of bulk powder. The total aerobic microbial count does not exceed 10¹ cfu/g. The total aerobic yeast and mold count does not exceed 10¹ cfu/g.

Foreign Particulate Matter

Diluent: Methanol and water (65:35), filtered through 0.45-µm filter

Filter: Mixed cellulose ester filter, 25-mm diameter, 0.45-µm pore size

Sample solution: Transfer contents of 4 unit doses from each of 2 inhalers into a receptacle, dissolve in about 75 mL of Diluent.

Calculate particles per dose:

Result = (N_<10 + N_10-100 + N_>100)/ 8

N_<10 = particles <10 µm

N_10-100 = particles 10–100 µm

N_>100 = particles >100 µm

Table 3 (IRA 1-Sep-2022)

7 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight, light-resistant containers. Store at controlled room temperature, in a dry place away from direct heat or sunlight.

Change to read:

USP Reference Standards 〈11〉

(IRA 1-Sep-2022)

USP Salmeterol Related Compound H RS

1-Hydroxy-4-[2-hydroxy-5-(1-hydroxy-2-{[6-(4-phenylbutoxy) hexyl)amino}ethyl)benzyl]-2-naphthoic acid, monohydrate.

C₃₆H₄₃NO₆ · H₂O 603.76

USP Salmeterol Resolution Check RS

This is a mixture of salmeterol xinafoate, salmeterol related compound H, and salmeterol-deoxy, also known as

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

USP Salmeterol System Suitability RS

This is a mixture of salmeterol xinafoate, salmeterol related compound H, and salmeterol-N-alkyl, also known as 

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

USP Salmeterol Xinafoate RS