Fluticasone Propionate and 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

Fluticasone Propionate and Salmeterol Inhalation Powder is a mixture of fluticasone propionate and salmeterol xinafoate for use in dry powder inhalers. The Inhalation Powder contains NLT 90% and NMT 110% of the labeled amount of fluticasone propionate (C₂₅H₃₁F₃O₅S) and NLT 90% and NMT 110% of the labeled amount of salmeterol (C₂₅H₃₇NO₄) as salmeterol xinafoate.

2 IDENTIFICATION

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Ultraviolet-Visible Spectroscopy: 197U

Diluent: Methanol and water (70:30)

Standard solution: A mixture of USP Fluticasone Propionate RS and USP Salmeterol Xinafoate RS according to the individual product strengths in the Inhalation Powder under test in Diluent

Sample solution: Dissolve a suitable number of unit doses of the Inhalation Powder under test in a suitable volume of Diluent.

Acceptance criteria: Meets the requirements

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B. 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 September 2022)

3 ASSAY

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3.1 PROCEDURE

Buffer: To each liter of 2.9 g/L of sodium dodecyl sulfate in water, add 1 mL of glacial acetic acid.

Solution A: Methanol and Buffer (20:80)

Mobile phase: Acetonitrile and Solution A (50:50)

Diluent: Methanol and water (70:30)

Standard solution: 10 µg/mL of USP Fluticasone Propionate RS and 3 µg/mL of USP Salmeterol Xinafoate RS in Diluent

Sample solution: Nominally 5-25 µg/mL of fluticasone propionate and 2.4 µg/mL of salmeterol from NLT 12 unit doses in Diluent

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detectors

Fluticasone propionate: UV 239 nm

Salmeterol: Fluorescence with excitation at 225 nm and emission at 305 nm. Use emission response for quantification.

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

Column temperature: 40°

Flow rate: 2 mL/min

Injection volume: 10 µL

Run time: NLT 1.5 times the retention time of salmeterol

3.3 System suitability

Sample: Standard solution

[NOTE-The relative retention times for fluticasone propionate and salmeterol are 0.6 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 3.5 between salmeterol and fluticasone propionate

Tailing factor: NMT 1.5 for salmeterol and fluticasone propionate

Relative standard deviation: NMT 2.0% for salmeterol and fluticasone propionate

3.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of fluticasone propionate (C₂₅H₃₁F₃O₅S) in the portion of Inhalation Powder taken:

Result = (r_U/r_S) x (C_S/C_U) x 100

r_U = peak response of fluticasone propionate from the Sample solution

r_S = peak response of fluticasone propionate from the Standard solution

C_S = concentration of USP Fluticasone Propionate RS in the Standard solution (µg/mL)

C_U = nominal concentration of fluticasone propionate in the Sample solution (µg/mL)

Calculate the percentage of the labeled amount of salmeterol (C₂₅H₃₇NO₄) in the portion of Inhalation Powder (IRA 1-Sep-2022) taken:

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

r_U = peak response of salmeterol from the Sample solution

r_S = peak response of salmeterol 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)

M_r1 = molecular weight of salmeterol free base, 415.57

M_r2 = molecular weight of salmeterol xinafoate, 603.75

Acceptance criteria: 90%-110% each for fluticasone propionate and salmeterol

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4 PERFORMANCE TESTS (IRA 1-Sep-2022)

IMPURITIES

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4.1 ORGANIC IMPURITIES

[NOTE-Protect all solutions containing fluticasone propionate or salmeterol from light.]

Solution A: 5.7 g/L of monobasic ammonium phosphate in water adjusted with 10% phosphoric acid TS to a pH of 2.9

Solution B: Acetonitrile

Mobile phase: See Table 1.

Table 1 (IRA 1-Sep-2022)

Diluent: Methanol, water, and phosphoric acid (70: 30:0.05)

Acidified methanol: To each liter of methanol, add 0.5 mL of phosphoric acid.

System suitability solution: 0.15 mg/mL of USP Salmeterol Xinafoate RS, 0.05 mg/mL of USP Fluticasone Propionate RS, and 0.4 µg/mL each of USP Fluticasone Propionate Related Compound D RS and USP Fluticasone Propionate Related Compound J RS in Diluent

Standard solution: 2 µg/mL of USP Salmeterol Related Compound H RS and 4 µg/mL of USP Fluticasone Propionate RS in Diluent

Sensitivity solution: 0.05 µg/mL of USP Salmeterol Related Compound H.RS and 0.1 µg/mL of USP Fluticasone Propionate RS from the Standard solution in Diluent

Sample solution: Nominally 200-500 µg/mL of fluticasone propionate prepared as follows. Transfer the contents of NLT 10 unit doses to a 10-mL volumetric flask. Add 6 mL of acidified methanol and sonicate for 10 min. Add 3 mL of water, mix, and allow the solution to equilibrate. Dilute with acidified methanol to volume.

4.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 228 nm

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

Column temperature: 35°

Flow rate: 1 mL/min

Injection volume: 50 µL

4.3 System suitability

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

[NOTE-See Table 2 (IRA 1-Sep-2022) for the relative retention times.]

Suitability requirements

Resolution: NLT 1.5 between fluticasone propionate related compound J and salmeterol; NLT 1.5 between fluticasone propionate related compound D and fluticasone propionate, System suitability solution

Tailing factor: NMT 2.0 for salmeterol related compound H and fluticasone propionate, Standard solution

Relative standard deviation: NMT 5.0% for salmeterol related compound H and fluticasone propionate, Standard solution

Signal-to-noise ratio: NLT 10 for both fluticasone propionate and salmeterol related compound H, Sensitivity solution

4.4 Analysis

Samples: Standard solution, Sensitivity solution, and Sample solution

Calculate the percentage of each fluticasone propionate related degradation product in the portion of Inhalation Powder taken:

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

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

r_S = peak response of fluticasone propionate from the Standard solution

C_S = concentration of USP Fluticasone Propionate RS in the Standard solution (µg/mL)

V = volume of the Sample solution (mL)

W_N = nominal weight of each unit dose (mg)

W_U = weight of the unit doses in the Sample solution (mg)

L = label claim of fluticasone propionate (µg/unit dose)

Disregard any fluticasone propionate related degradation product peak less than the area of fluticasone propionate in the Sensitivity solution.

Calculate the percentage of each salmeterol related degradation product in the portion of Inhalation Powder taken:

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

r_U =peak (IRA 1-Sep-2022) response of each salmeterol related degradation product from the Sample solution

r_S = speak (IRA 1-Sep-2022) response of salmeterol related compound H from the Standard solution

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

V = volume of the Sample solution (mL)

W_N = nominal weight of each unit dose (mg)

W_U = weight of the unit doses in the Sample solution (mg)

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

Acceptance criteria: See Table 2. (IRA 1-Sep-2022) Disregard any salmeterol related degradation product peak less than the area of salmeterol related compound H in the Sensitivity solution. [NOTE-Any unspecified degradation product eluting before salmeterol is related to salmeterol. Any unspecified degradation product eluting after salmeterol is related to fluticasone propionate.]

Table 2 (IRA 1 September 2022)

^a This is a process impurity that is included in this table for identification only. This impurity is controlled in the drug substance. This impurity is not to be reported for the drug product or to be included in the total degradation products.

^b 4-[1-Hydroxy-2-(4-phenylbutylamino)ethyl]-2-(hydroxymethyl)phenol.

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

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

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

^f This is a counter ion of salmeterol that is included in this table for identification only. It is not to be reported for the drug product or to be included in the total degradation products.

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

^h 6α,9α-Difluoro-11β-hydroxy-16α- methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbodithioic acid.

ⁱ 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.

^j 6α,9α-Difluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylic acid 6α,9α-difluoro-17β-(fluoromethylthio) carbonyl-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-yl ester.

5 SPECIFIC TESTS

5.1 MICROBIAL ENUMERATION TESTS (61) and TESTS FOR SPECIFIED MICROORGANISMS (62)

The total aerobic microbial count does not exceed 10¹ cfu/g of

powder. The total aerobic yeasts and molds count does not exceed 10¹ cfu/g of formulation. It meets the requirements of the tests for absence of Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Salmonella species.

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5.2 FOREIGN PARTICULATE MATTER

Particulate Matter in Injections (788) describes details of the test apparatus to be used for the determination of particulate matter using a microscopic particle count test methodology. Samples should be carefully prepared to avoid environmental contamination, and testing should be performed with suitable controls, including the appropriate use of blank determinations.

Diluent: Methanol and water (65:35) passed through a filter of 0.45-µm pore size

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

Sample solution: Transfer contents of NLT 8 unit doses to a suitable container. Dissolve in 75 mL of Diluent.

Analysis

Sample: Sample solution

Pass the Sample solution through the filter and allow the filter to dry under conditions that will limit particulate contamination. Using a microscopic particle count test method, enumerate the number of particles present in the Sample solution.

Calculate the total number of particles per actuation by the formula:

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

N_<10 = total number of particles <10 µm present in the Sample solution

N_10-100 = total number of particles between 10 and 100 µm present in the Sample solution

N_>100 = total number of particles >100 µm present in the Sample solution

Acceptance criteria: See Table 3.

Table 3 (IRA 1-Sep-2022)

6 ADDITIONAL REQUIREMENTS

6.1 Packaging and Storage

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

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LABELING (IRA 1-SEP-2022)

6.2 USP REFERENCE STANDARDS (11)

USP Fluticasone Propionate RS

USP Fluticasone Propionate Related Compound D RS

S-Methyl 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate.

C₂₅H₃₂F₂O₅S 482.58

USP Fluticasone Propionate Related Compound J RS

6α,9α-Difluoro-11β,17α-dihydroxy-16α-methyl-3-methyl-1,4-diene-17β-carboxylic acid.

C₂₁H₂₆F₂O₅ 396.42

USP Salmeterol Related Compound HRS

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

C₃₆H₄₃NO₆·H₂O 603.76

USP Salmeterol Xinafoate RS