Fluticasone Propionate and Salmeterol Inhalation Aerosol

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 Aerosol is a suspension of Fluticasone Propionate and Salmeterol with suitable propellants in a pressurized container. The mean content per actuation contains NLT 88% and NMT 112% of the labeled amount of fluticasone propionate (C₂₅H₃₁F₃O₅S). The mean content per actuation contains NLT 88% and NMT 112% of the labeled amount of salmeterol (C₂₅H₃₇NO₄) as salmeterol xinafoate.

2 IDENTIFICATION

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197A

Wavenumber range: 4000-600 cm^-1

Sample: Discharge an appropriate number of actuations from two containers into an agate mortar. Allow the propellant to evaporate and dry if necessary. Transfer the residue to the sample window.

Acceptance criteria: Meets the requirements. In addition, the ratio of the fluticasone propionate band at 833 cm¯¹ to that of the salmeterol band at 744 cm^-1 meets the requirements in Table 1.

Table 1

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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

3.1 PROCEDURE

Buffer: 0.01 M sodium dodecyl sulfate containing 0.1% 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: 50 µg/mL of USP Fluticasone Propionate RS and 15 µg/mL of USP Salmeterol Xinafoate RS in Diluent

Sample solution: Nominally 20-110 µg/mL of fluticasone propionate and 10 µg/mL of salmeterol prepared as follows. Shake the canister vigorously, and cool for 10 min in a dry ice-methanol bath. Remove the canister from the bath, and shake vigorously. Using a suitable device, carefully remove and keep the valve, and pour the contents into a suitable container. Allow the propellant to evaporate. Dissolve the canister contents in a minimum amount of methanol and quantitatively transfer to a suitable volumetric flask containing 30% of the flask volume of water. Rinse the canister and valve with methanol into the same volumetric flask. Allow the flask to come to room temperature and dilute with methanol to volume.

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: 5 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 fluticasone propionate and salmeterol

Tailing factor: NMT 1.5 for fluticasone propionate and salmeterol

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

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 Aerosol 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 Aerosol 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

onate a Acceptance criteria: 88%-112% 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.]

Buffer: 0.05 M monobasic ammonium phosphate adjusted with 10% (v/v) of phosphoric acid to a pH of 2.9

Solution A: Acetonitrile and Buffer (30:70)

Solution B: Acetonitrile and Buffer (78:22)

Mobile phase: See Table 2.

Table 2 (IRA 1-Sep-2022)

Diluent 1: Methanol, water, and phosphoric acid (70: 30: 0.05)

Diluent 2: Methanol and water (70:30)

Diluent 3: 0.05% phosphoric acid in methanol

System suitability solution: 0.075 mg/mL of USP Salmeterol Xinafoate RS, 0.025 mg/mL of USP Fluticasone Propionate RS, and 0.2 µg/mL each of USP Fluticasone Propionate Related Compound D RS and USP Fluticasone Propionate Related Compound J RS in Diluent 1

Sensitivity solution: 0.05 µg/mL of USP Salmeterol Xinafoate RS and 0.1 µg/mL of USP Fluticasone Propionate RS in Diluent 2

Sample solution: Nominally 50-100 µg/mL of salmeterol prepared as follows. Place a canister into a freezing mixture of dry ice and methanol, and cool for approximately 5 min. Carefully remove the valve from the canister. Pour the contents into a suitable container and allow the propellant to evaporate. Dissolve the residue in Diluent 3 and dilute with water to the required volume to obtain the nominal concentration.

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 and Sensitivity solution

[NOTE-See Table 3 (IRA 1-Sep-2022) for relative retention times.]

Suitability requirements

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

Tailing factor: NMT 1.5 for fluticasone propionate and salmeterol, System suitability solution

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

4.4 Analysis

Sample: Sample solution

Calculate the percentage of each degradation product in the portion of Inhalation Aerosol taken:

Result = (r_U/r_S) x 100

r_U = peak response of each impurity from the Sample solution

r_S = peak response of either salmeterol or fluticasone propionate from the Sample solution

Acceptance criteria: See Table 3 (IRA 1-Sep-2022). Disregard any peak less than 0.05%. [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 3 (IRA 1 September 2022)

^a This is a process impurity that is included in this table for identification purposes 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 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 purposes 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 16α,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 formulation. 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

The test described below and the specification is only applicable to a microscopic particle count test methodology. 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.

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

Sample solution: Perform testing on two previously unused inhalers. Prime each inhaler by discharging a predetermined number of actuations to waste. Discharge, and dissolve 16 actuations, eight from each of two canisters in 50 mL of methanol.

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 number of particles per actuation:

Result = (N_<10 + N_10-100 + N_>100)/16

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 4.

Table 4 (IRA 1-Sep-2022)

6 ADDITIONAL REQUIREMENTS

6.1 PACKAGING AND STORAGE

Preserve in nonreactive, light-resistant aerosol containers with metered valves fitted with a dose counter and provided with oral inhalation actuators. Avoid exposure to heat. Store at controlled room temperature.

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-oxoandrosta-1,4-diene-17β-carboxylic acid.

C₂₁H₂₆F₂O₅ 396.42

USP Salmeterol Xinafoate RS