Tadalafil

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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C₂₂H₁₉N₃O₄ 389.40

Pyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione, 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R-12aR)-;

(6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-[3,4-(methylenedioxy)phenyl] pyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione CAS RN®: 171596-

29-5; UNII: 742SXX0ICT.

1 DEFINITION

Tadalafil contains NLT 97.5% and NMT 102.5% of Tadalafil (C₂₂H₁₉N₃O₄ ), calculated on the dried basis.

2 IDENTIFICATION

Change to read:

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K (CN 1-May-2020)

B. The retention time of the major peak of the Sample solution corresponds to that of the Identi

cation solution, as obtained in the test for

Enantiomeric and Diastereomeric Purity.

3 ASSAY

3.1 Procedure

Solution A: Add 1.0 mL of tri

uoroacetic acid to 1 L of water.

Mobile phase: Acetonitrile and Solution A (45:55)

Standard solution: 0.1 mg/mL of USP Tadalafil RS in acetonitrile and Solution A (1:1); prepare by first dissolving the standard in acetonitrile, and then diluting with Solution A to final volume.

Sample solution: 0.1 mg/mL of Tadalafil in acetonitrile and Solution A (1:1); prepare by first dissolving the sample in acetonitrile, and then diluting with Solution A to final volume.

3.2 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: 285 nm

Column: 4.6-mm × 25-cm; 5-μm packing L7

Column temperature: 40°

Flow rate: 1.5 mL/min

Injection volume: 20 μL

3.3 System suitability

Sample: Standard solution

3.4 Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 0.73%

3.5 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of Tadalafil (C₂₂H₁₉N₃O₄ ) in the portion of Tadalafil taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

C_S = concentration of USP Tadalafil RS in the Standard solution (mg/mL)

C_U = concentration of Tadalafil in the Sample solution (mg/mL)

Acceptance criteria: 97.5%–102.5% on the dried basis

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.10%, using a 1-g sample

4.1 Organic Impurities

[Note—Do not use sonication during the preparation of analyte solutions.]

Solution A: Add 1.0 mL of trifluoroacetic acid to 1 L of water.

Solution B: Acetonitrile

Mobile phase: See Table 1. Return to original conditions and re-equilibrate the column.

Table 1

Standard solution: 0.4 μg/mL of USP Tadalafil

RS in acetonitrile and Solution A (1:1); prepare by first dissolving the standard in acetonitrile, and then diluting with Solution A to final volume.

Sensitivity solution: 0.2 μg/mL of USP Tadalafil

RS in acetonitrile and Solution A (1:1) from the Standard solution

System suitability stock solution: To generate the 6R,12aS diastereomer of Tadalafil, dissolve 4.0 mg of Tadalafil in 50 mL of a mixture of isopropyl alcohol and acetonitrile (1:1). Add 1.0 mL of 1.0 M tetrabutylammonium hydroxide in methanol, and allow to stand at room temperature for 40 min. Add 1.0 mL of tri fluoroacetic acid, and dilute with a mixture of isopropyl alcohol and acetonitrile (1:1) to 100 mL.

System suitability solution: Dissolve 40 mg of Tadalafil in 50 mL of acetonitrile. Add 2.0 mL of the System suitability stock solution, and dilute with Solution A to 100 mL.

Sample solution: 0.4 mg/mL of Tadalafil in acetonitrile and Solution A (1:1); prepare by first dissolving the sample in acetonitrile, and then diluting with Solution A to final volume.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 285 nm

Column: 4.6-mm × 25-cm; 5-μm packing L7

Column temperature: 40°

Flow rate: 1.0 mL/min

Injection volume: 20 μL

System suitability

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

[Note—The relative retention times for Tadalafil and the 6R,12aS diastereomer of Tadalafil are about 1.0 and 1.03, respectively.]

Suitability requirements

Tailing factor: NMT 1.5, Standard solution

Relative standard deviation: NMT 2.0%, Standard solution

Peak-to-valley ratio: The ratio of the height of the 6R,12aS diastereomer peak to the height of the valley between the 6R,12aS diastereomer peak and Tadalafil is NLT 3.3, System suitability solution

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

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Tadalafil taken:

Result = (r_U/r_S) × (C_S/C_U ) × 100

r_U = peak response of each impurity from the Sample solution

r_S = peak response of Tadalafil from the Standard solution

C_S = concentration of USP Tadalafil RS in the Standard solution (mg/mL)

C_U = concentration of Tadalafil in the Sample solution (mg/mL)

4.2 Acceptance criteria

[Note—Disregard peaks due to the 6R,12aS and 6S,12aR diastereomers of Tadalafil, which co-elute at a retention time of about 1.03 relative to Tadalafil. The diastereomers are controlled in the test for Enantiomeric and Diastereomeric Purity.]

Individual impurities: NMT 0.1%

Total impurities: NMT 0.3%

Reporting level for impurities: 0.05%

Enantiomeric and Diastereomeric Purity

Mobile phase: Hexanes and isopropyl alcohol (50:50)

Diluent: Hexanes, isopropyl alcohol, and acetonitrile (40:40:20)

Identification solution: 0.5 mg/mL of USP Tadalafil

RS in Diluent. [Note—This solution is used for Identification test B.]

Standard stock solution: 50 μg/mL of USP Tadalafil RS in Diluent

Standard solution: 0.5 μg/mL of USP Tadalafil RS in Diluent from the Standard stock solution

System suitability stock solution: To generate the 6R,12aS diastereomer of Tadalafil, dissolve 25 mg of Tadalafil in 40 mL of Diluent. Add 1.0 mL of 1.0 M tetrabutylammonium hydroxide in methanol, and allow to stand at room temperature for 20 min. Add 1.0 mL of trifluoroacetic acid, and dilute with Diluent to 50 mL.

System suitability solution: Transfer 1.0 mL of the System suitability stock solution and 10 mL of the Standard stock solution to a 50-mL volumetric flask, and dilute with Diluent to volume.

Sensitivity solution: 0.25 μg/mL of USP Tadalafil RS in Diluent from Standard solution

Sample solution: 0.5 mg/mL of Tadalafil  in Diluent

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: 222 nm

Column: 4.6-mm × 25-cm; 10-μm packing L51

Column temperature: 30°

Flow rate: 0.75 mL/min

Injection volume: 10 μL

System suitability

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

Suitability requirements

Resolution: NLT 2.0, between the 6R,12aS diastereomer and Tadalafil, System suitability solution

Tailing factor: NLT 0.8 and NMT 1.5, Standard solution

Relative standard deviation: NMT 10.0%, Standard solution

Signal-to-noise ratio: NLT 20, Sensitivity solution

Analysis

Samples: Identification solution, Standard solution, and Sample solution

Calculate the percentage of each stereoisomer impurity in the portion of Tadalafil taken:

Result = (r_U/r_S) × (C_S/C_U ) × 100

r_U = peak response of each stereoisomer impurity from the Sample solution

r_S = peak response of Tadalafil from the Standard solution

C_S = concentration of USP Tadalafil RS in the Standard solution (mg/mL)

C_U = concentration of Tadalafil in the Sample solution (mg/mL)

Acceptance criteria: See Table 2.

Table 2

^a (6R,12aS)-6-(1,3-Benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione.

^b (6S,12aS)-6-(1,3-Benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione.

^c (6S,12aR)-6-(1,3-Benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione.

5 SPECIFIC TESTS

Loss on Drying 〈731〉

Analysis: Dry a sample under vacuum at 105° for 3 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers. Store at room temperature.

USP Reference Standards 〈11〉

USP Tadalafil RS