Fluticasone Propionate 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 Inhalation Powder contains NLT 90% and NMT 110% of the labeled amount of fluticasone propionate (C₂₅H₃₁F₃O₅S).

2 IDENTIFICATION

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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 September 2022)

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 (49:51)

Diluent: Methanol and water (70:30)

Standard solution: 6-12 µg/mL of USP Fluticasone Propionate RS in Diluent

Sample solution: Nominally 6-12 µg/mL of fluticasone propionate from NLT 12 unit doses in Diluent

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 239 nm

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

Flow rate: 2 mL/min

Column temperature: 40°

Injection volume: 50 µL

System suitability

Sample: Standard solution

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

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 2.0%

3.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage 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 (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: 90%-110%

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4 PERFORMANCE TESTS (IRA 1-Sep-2022)

IMPURITIES

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4.1 ORGANIC IMPURITIES

[NOTE-Protect sample and standard solutions 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 12 mL of Solution A. Add 8 mL of Solution C, and mix.

Sensitivity solution: 0.5 µg/mL of USP Fluticasone Propionate RS in Solution A

Sample solution: Nominally 100 µg/mL of fluticasone propionate from NLT 10 unit doses prepared as follows. Transfer the contents of the appropriate number of unit doses into a suitable volumetric flask. Add 60% of the flask volume of Solution A, (IRA 1-Sep-2022) and sonicate for 2 min. Add 40% of the flask volume of Solution C. (IRA 1-Sep-2022) mix, and allow the solution to equilibrate. Dilute with Solution C (IRA 1-Sep-2022) to volume if necessary. Mix, allow any undissolved excipient material to settle, and inject the supernatant.

4.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 239 nm

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

Flow rate: 1 mL/min

Column temperature: 40°

Injection volume: 100 µL

4.3 System suitability

Samples: System suitability solution and Sensitivity solution

Suitability requirements

Resolution: NLT 0.6 between fluticasone propionate related compound B and fluticasone propionate related compound C; NLT 1.5 between fluticasone propionate related compound D and fluticasone propionate, System suitability solution

Tailing factor: NMT 1.3 for fluticasone propionate, System suitability solution

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

4.4 Analysis

Sample: Sample solution

Calculate the percentage of each fluticasone propionate related impurity in the portion of sample taken:

Result = (r_U/r_T) x 100

r_U = peak response of each impurity from the Sample solution

r_T = total peak response for all peaks 20.05% 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-17a-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. They are not to be reported for the drug product and are not included in the total impurities.

^c 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.

^d Sum of all impurity peaks ≥0.05%.

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 bulked powder, the total aerobic yeasts and molds count does not exceed 10¹ cfu/g of bulked powder. It meets the requirements of the tests for absence of Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Salmonella species, and Enterobacteriaceae in 1 g of bulked powder.

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5.2 PARTICULATE MATTER IN INJECTIONS (788)

The test described below and the specification are applicable only 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.

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

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

Sample solution: Transfer the contents of 4 unit doses from each of two inhalers into a suitable receptacle, and dissolve the drug and excipient particles in about 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 number of particles per dose:

Number of particles/dose = (N_<10 + N_10-100 + N_>100)/8

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

N_10-100 = total number of particles between 10 and 100 µm 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.

6.2 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].