Fluticasone Propionate 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 Inhalation Aerosol is a suspension of Fluticasone Propionate with suitable propellants in a pressurized container. The mean content per actuation contains NLT 85% and NMT 115% of the labeled amount of fluticasone propionate (C₂₅H₃₁F₃O₅S).

2 IDENTIFICATION

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

Spectral range: 4000 cm^-1 to 600 cm^-1

Samples: Deposit between 5 and 20 actuations onto the zinc selenide plate of the HATR (Horizontal ATR) accessory. Dry the zinc selenide plate.

Acceptance criteria: Meets the requirements

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

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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 (1:1)

Standard solution: 50 µg/mL of USP Fluticasone Propionate RS in acetonitrile and water (1:1)

Sample solution: Nominally 50 µg/mL of fluticasone propionate 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. Transfer the canister content to a suitable volumetric flask fitted with a suitable funnel using about 12% of the flask volume of acetonitrile. Add 50% of the flask volume of water. Swab the outer part of the valve with damp cotton wool soaked in acetonitrile. Place the swab in the neck of the funnel in the volumetric flask. Allow the valve to dry, then dismantle, and wash the components and the canister wall with acetonitrile. Collect the washings, and place in the same volumetric flask as the sample. Allow the flask to come to room temperature, and dilute with acetonitrile to volume.

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 239 nm

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

Column temperature: 40°

Flow rate: 2 mL/min

Injection volume: 10 µL

3.3 System suitability

Sample: Standard solution

[NOTE-The retention time for the peak due to fluticasone propionate must be within the range of 1.0-1.6 min.]

Suitability requirements

Tailing factor: NMT 1.3 for the fluticasone propionate peak

Relative standard deviation: NMT 2.0%

3.4 Analysis

Samples: Standard solution and Sample solution

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

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

r_U = peak (IRA 1-Sep-2022) response from the Sample solution

r_S = peak (IRA 1-Sep-2022) response 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)

Acceptance criteria: 85%-115%

Delete the following:

3.5 PERFORMANCE TESTS (IRA 1-Sep-2022)

IMPURITIES

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3.6 ORGANIC IMPURITIES: Protect the Sample solution (IRA 1-Sep-2022) from light.

Solution A: Prepare a solution of 0.05% v/v phosphoric acid in acetonitrile.

Solution B: Prepare a solution of 0.05% v/v phosphoric acid in methanol.

Solution C: Prepare a solution of 0.05% v/v phosphoric acid in water.

Mobile phase: See Table 1.

Table 1 (IRA 1-Sep-2022)

System suitability solution: Dissolve 2 mg of USP Fluticasone Propionate System Suitability Mixture RS in 5 mL of Solution A. Add 5 mL of Solution C, and mix.

Sample solution: Nominally 200 µg/mL of fluticasone propionate in Solution A 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, and pass the contents through a filter of 0.22-µm pore size. When the filter bed is dry, wash it with two 5-mL aliquots of cyclohexane. Allow the paper to dry, then carefully transfer to an appropriate container. Dissolve the drug present on the filter paper in 50% of the final required volume of Solution A. Dilute with Solution C to volume to obtain the nominal concentration.

3.7 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 239 nm

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

Column temperature: 40°

Flow rate: 1 mL/min

Injection volume: 50 µL

3.8 System suitability

Sample: System suitability solution

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

Suitability requirements

Resolution: NLT 0.6 between the fluticasone propionate related compound B and fluticasone propionate related compound C peaks and NLT 1.5 between the fluticasone propionate related compound D and fluticasone propionate peaks

Tailing factor: NMT 1.1 for the fluticasone propionate peak

3.9 Analysis

Sample: Sample solution

Calculate the percentage of each impurity in the portion of Inhalation Aerosol taken:

Result = (r_U/r_T) x 100

r_U = peak (IRA 1-Sep-2022) response of each impurity from the Sample solution

r_T = total peak area for all peaks ≥0.05% by area of the peak due to fluticasone propionate from the Sample solution

Acceptance criteria: See Table 2.

Table 2 (IRA 1-Sep-2022)

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

^b These are process impurities that are included in the table for identification only. These impurities are controlled in the drug substance and are not included in the total impurities.

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

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

^e Sum of all impurity peaks 20.05%.

4 SPECIFIC TESTS

4.1 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 in 10 g of the formulation.

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4.2 PARTICULATE MATTER IN INJECTIONS (788)

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 filter; 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, 8 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 by the formula:

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 3.

Table 3 (IRA 1-Sep-2022)

OTHER REQUIREMENTS (IRA 1-SEP-2022)

5 ADDITIONAL REQUIREMENTS

5.1 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.

5.2 USP REFERENCE STANDARDS (11)

USP Fluticasone Propionate RS

USP Fluticasone Propionate System Suitability Mixture RS

It is a mixture of: Fluticasone propionate; Fluticasone propionate related compound B: [6α,9α-difluoro-11β-hydroxy-16α-methyl-2',3,4'-trioxo-17α-spiro(androsta-1,4-diene-17,5'-(1,3) oxathiolane]; Fluticasone propionate related compound C: [S-fluoromethyl 17α-acetyloxy-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate]; Fluticasone propionate related compound D: [S-methyl 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate].