Roumilast

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

Roflumilast contains NLT 98.0% and NMT 102.0% of roflumilast (C₁₇H₁₄Cl₂F₂N₂O₃), calculated on the anhydrous basis.

2 IDENTIFICATION

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197A or 197K

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

Procedure

Protect all solutions containing roflumilast from light.

Solution A:

1.74 g/L potassium phosphate dibasic + 1.02 g/L tetrabutylammonium hydrogen sulfate in water.

Adjust to pH 5.9 with phosphoric acid.

Solution B:

1.02 g/L tetrabutylammonium hydrogen sulfate in methanol.

Mobile phase: See Table 1.

[Note—Equilibrate the LC system ≥1 h; inject solvent blank at least 3 times before analysis.]

System suitability solution: 0.2 mg/mL of USP Roflumilast RS and 0.001 mg/mL of USP Roflumilast Related Compound D RS in methanol

Standard solution: 0.2 mg/mL of USP Roflumilast RS in methanol

Sample solution: 0.2 mg/mL of Roflumilast in methanol

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 248 nm

Column: 2.0-mm × 12.5-cm; 5-µm packing L1.

[Note—A guard column of 2.0-mm × 1.0-cm; 5-μm packing L1 may be used.]

Column temperature: 40°

Flow rate: 0.4 mL/min

Injection volume: 10 µL

System suitability

Samples: System suitability solution and Standard solution

[Note—The relative retention times for roflumilast related compound D and roflumilast are 0.9 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 2.0 between roflumilast related compound D and roflumilast, System suitability solution

Tailing factor: NMT 1.5, Standard solution

Relative standard deviation: NMT 0.85% from 6 replicate injections, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of roflumilast (C₁₇H₁₄Cl₂F₂N₂O₃) in the portion of Roflumilast taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

Where:

rᵤ = peak response of roflumilast from the Sample solution

rₛ = peak response of roflumilast from the Standard solution

Cₛ = concentration of USP Roflumilast RS in the Standard solution (mg/mL)

Cᵤ = concentration of Roflumilast in the Sample solution (mg/mL)

Acceptance criteria: 98.0%–102.0% on the anhydrous basis

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.2%

Organic Impurities

Protect all solutions containing roflumilast from light.

Buffer: 1.74 g/L of potassium phosphate dibasic and 1.02 g/L of tetrabutylammonium hydrogen sulfate in water. Adjust with phosphoric acid to a pH of 5.9.

Solution A: Tetrahydrofuran and Buffer (5:95)

Solution B: 1.02 g/L of tetrabutylammonium hydrogen sulfate in acetonitrile

Mobile phase: See Table 2.

[Note—A re-equilibration time of 5 min may be suitable. After each run, return to the original conditions and re-equilibrate the system.]

Table 2

Diluent: Buffer and Solution B (50:50)

Impurity stock solution 1: 0.4 mg/mL each of USP Roflumilast Related Compound A RS, B RS, C RS, D RS, and E RS, prepared as follows. Transfer a suitable quantity of each Reference Standard to an appropriate volumetric flask and dissolve in Solution B to volume.

Impurity stock solution 2:

0.04 mg/mL each of USP Roflumilast Related Compound A RS, B RS, C RS, D RS, and E RS from Impurity stock solution 1, in Diluent

Standard stock solution:

1.0 mg/mL of USP Roflumilast RS, prepared as follows. Transfer an appropriate quantity of USP Roflumilast RS to a suitable volumetric flask, dissolve in 50% of the flask volume of Solution B, and then dilute with Buffer to volume.

Standard solution:

0.001 mg/mL of USP Roflumilast RS from the Standard stock solution, in Diluent

System suitability solution:

1.0 mg/mL of USP Roflumilast RS and 1.5 µg/mL each of USP Roflumilast Related Compounds A–E, prepared as follows. Pipet an appropriate volume of Impurity stock solution 2 into a suitable volumetric flask and dilute with Standard stock solution to volume.

Sensitivity solution:

0.3 µg/mL of USP Roflumilast RS from the Standard stock solution in Diluent

Sample solution:

1.0 mg/mL of Roflumilast prepared as follows. Transfer an appropriate quantity of Roflumilast to a suitable volumetric flask and dissolve in 50% of the flask volume of Solution B. Dilute with Buffer to volume.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 252 nm

Column: 4.6-mm × 15-cm; 3.5-µm packing L1

Column temperature: 30°

Flow rate: 1.5 mL/min

Injection volume: 30 µL

System suitability

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

[Note—See Table 3 for the relative retention times.]

Suitability requirements:

Resolution: NLT 2.0 between roflumilast related compound B and A;

NLT 1.5 between roflumilast and compound E (System suitability solution)

Tailing factor: NMT 1.5 for roflumilast and each related compound

Relative standard deviation: NMT 5.0%, Standard solution

Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of any specified and unspecified impurity:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × (1/F) × 100

Where:

rᵤ = peak response of specified or unspecified impurity from Sample solution

rₛ = peak response of roflumilast from Standard solution

Cₛ = concentration of USP Roflumilast RS in Standard solution (mg/mL)

Cᵤ = concentration of Roflumilast in Sample solution (mg/mL)

F = relative response factor (see Table 3)

Acceptance criteria: See Table 3. The reporting threshold is 0.05%.

(a) This impurity is listed for information only. It is controlled using the Limit of Roflumilast Related Compound E procedure and excluded from the total impurities calculation.

(b) Excluding roflumilast related compound E.

Change to read:

Limit of Roflumilast Related Compound E

[Note—Perform this test in addition to the Organic Impurities test if roflumilast related compound E is present in the drug substance due to the manufacturing process.]

Protect all solutions containing roflumilast from light.

Mobile phase: n-Hexane and dehydrated alcohol (90:10)

Impurity stock solution 1:

360 µg/mL of USP Roflumilast Related Compound E RS, prepared as follows. Transfer an appropriate quantity of USP Roflumilast Related Compound E RS to a suitable volumetric flask, dissolve in 10% of the flask volume of dehydrated alcohol, and then dilute with n-hexane to volume.

Impurity stock solution 2:

36 µg/mL of USP Roflumilast Related Compound E RS from Impurity stock solution 1 in Mobile phase

Impurity sensitivity solution:

0.3 µg/mL of USP Roflumilast Related Compound E RS from Impurity stock solution 1 in Mobile phase

Standard stock solution:

600 µg/mL of USP Roflumilast RS, prepared as follows. Transfer an appropriate quantity of USP Roflumilast RS to a suitable volumetric flask, dissolve in 10% of the flask volume of dehydrated alcohol, and then dilute with n-hexane to volume.

Standard solution:

0.6 µg/mL of USP Roflumilast RS from the Standard stock solution in Mobile phase

System suitability solution:

600 µg/mL of USP Roflumilast RS and 0.9 µg/mL of USP Roflumilast Related Compound E RS, prepared as follows. Pipet an appropriate volume of Impurity stock solution 2 to a suitable volumetric flask and dilute with Standard stock solution to volume.

Sample solution:

600 µg/mL of Roflumilast, prepared as follows. Transfer an appropriate quantity of Roflumilast to a suitable volumetric flask, dissolve in 10% of the flask volume of dehydrated alcohol, and then dilute with n-hexane to volume.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 212 nm

Column:

4.6-mm × 10-cm; 3.0-µm packing L8

Column temperature:

40°C

Flow rate:

1 mL/min

Injection volume:

8 µL

Run time:

NLT 1.8 times the retention time of roflumilast

System suitability

Samples:

Impurity sensitivity solution, Standard solution, and System suitability solution

[Note—The relative retention times for roflumilast and roflumilast related compound E are 1.0 and 1.3, respectively.]

Suitability requirements:

Resolution: NLT 2.5 between roflumilast and roflumilast related compound E, System suitability solution

Tailing factor: NMT 1.5 for roflumilast related compound E, System suitability solution

Relative standard deviation: NMT 5.0%, Standard solution

Signal-to-noise ratio: NLT 10, Impurity sensitivity solution

Analysis

Samples:

Standard solution and Sample solution

Calculate the percentage of roflumilast related compound E in the portion of Roflumilast taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × (1 / F) × 100

Where:

rᵤ = peak response of roflumilast related compound E from the Sample solution

rₛ = peak response of roflumilast from the Standard solution

Cₛ = concentration of USP Roflumilast RS in the Standard solution (µg/mL)

Cᵤ = concentration of Roflumilast in the Sample solution (µg/mL)

F = relative response factor for roflumilast related compound E, 0.89

Acceptance criteria:

NMT 0.15%

5 SPECIFIC TESTS

Water Determination 〈921〉, Method I: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage:

Preserve in tight containers. Store at controlled room temperature. Protect from light.

USP Reference Standards 〈11〉

USP Roflumilast RS

 USP Roflumilast Related Compound A RS

3-(Cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-hydroxybenzamide.

C₁₆H₁₄Cl₂N₂O₂ 353.20

 USP Roflumilast Related Compound B RS

N-(3,5-Dichloropyridin-4-yl)-4-(difluoromethoxy)-3-hydroxybenzamide.

C₁₃H₈Cl₂F₂N₂O₃ 349.11

USP Roflumilast Related Compound C RS

3,5-Dichloropyridin-4-amine.

C₅H₄Cl₂N₂ 163.00

USP Roflumilast Related Compound D RS

3-(Cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid.

C₁₀H₁₀F₂O₄ 258.22

USP Roflumilast Related Compound E RS

N-(3-Bromo-5-chloropyridin-4-yl)-3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzamide.

C₁₇H₁₄BrClF₂N₂O₃ 447.66