Sildenafil Citrate

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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C₂₂H₃₀N₆O₄S .C₆H₈O₇ 666.70 

Piperazine, 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methyl-, 2-hydroxy-1,2,3- propanetricarboxylate (1:1); 

1-[[3-(6,7-Dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate (1:1) 

RN®: 171599-83-0; UNII: BW9B0ZE037. 

Sildenafil 

C₂₂H₃₀N₆O₄S  474.58 CAS RN®: 139755-83-2; UNII: 3M7OB98Y7H. 

1 DEFINITION 

Sildenafil Citrate contains NLT 98.0% and NMT 102.0% of Sildenafil citrate (C₂₂H₃₀N₆O₄S .C₆H₈O₇), calculated on the anhydrous and solvent-free basis. 

2 IDENTIFICATION 

Change to read: 

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

3 ASSAY 

Procedure 

Buffer: Dilute 7 mL of triethylamine with water to 1 L. Stir, and adjust with phosphoric acid to a pH of 3.0 ± 0.1. 

Mobile phase: Buffer, methanol, and acetonitrile (58:25:17) 

Standard solution: 0.028 mg/mL of USP Sildenafil Citrate RS in Mobile phase 

Sample solution: 0.028 mg/mL of Sildenafil Citrate in Mobile phase 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 290 nm 

Column: 3.9-mm × 15-cm; 5-µm packing L1 

Column temperature: 30° 

Flow rate: 1 mL/min 

Injection size: 20 µL 

System suitability 

Sample: Standard solution 

Suitability requirements 

Tailing factor: NMT 1.5 

Relative standard deviation: NMT 0.85% for six replicate injections 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of Sildenafil citrate (C₂₂H₃₀N₆O₄S .C₆H₈O₇) in the portion of the sample taken: 

Result = (r_U/r_S) × (C_S/C_U) × 100 

r_U = peak response of Sildenafil from the Sample solution

r_S = peak response of Sildenafil from the Standard solution  

C_S = concentration of the Standard solution (mg/mL) 

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

Acceptance criteria: 98.0%–102.0% on the anhydrous and solvent-free basis 

4 IMPURITIES 

Residue on Ignition 〈281〉 

Sample: NLT 0.5 g 

Acceptance criteria: NMT 0.1% 

Limit of Imidazole 

Diluent: Methanol, water, and ammonium hydroxide (15:5:1) 

Standard solution 1: 0.035 mg/mL of USP Imidazole RS in Diluent 

Standard solution 2: 0.0175 mg/mL of USP Imidazole RS in Diluent from Standard solution 1 Sample solution: 17.5 mg/mL of Sildenafil Citrate in Diluent 

System suitability solution: Mix equal volumes of Sample solution and Standard solution 1. Chromatographic system 

(See Chromatography 〈621〉, Thin-Layer Chromatography.) 

Mode: TLC 

Adsorbent: 0.2-mm layer of chromatographic silica gel mixture with a particle size of 2–10 µm (HPTLC plates) Application volume: 10 µL. [Note—Apply as 6-mm bands.] 

Developing solvent system: Methylene chloride, ethyl acetate, alcohol, and ammonium hydroxide (50:30:20:1) System suitability 

Sample: System suitability solution 

Suitability requirements: The chromatogram shows two clearly separated zones. 

Analysis: 

Samples: Standard solution 2 and Sample solution 

Develop the plate over a distance of about two-thirds of the length of the plate. Dry at 100° for about 15 min, and cool. Expose the plate to iodine vapor until the plate is light brown, and examine the plate under UV light at 254 nm. [Note—The retardation factors for citrate, imidazole, and Sildenafil are about 0, 0.25, and 0.4, respectively.] 

Acceptance criteria: Any spot corresponding to imidazole in the Sample solution is not more intense than the principal spot from Standard solution 2 (0.1%). 

Organic Impurities 

Buffer, Mobile phase, and Chromatographic system: Proceed as directed in the Assay, except to run the chromatograph for 3 times the retention time of Sildenafil. 

Identification solution: 7.5 µg/mL of USP Sildenafil Related Compound A RS in Mobile phase 

System suitability solution: Dissolve 70 mg of Sildenafil Citrate in 1 mL of a solution of Hydrogen peroxide and anhydrous formic acid (2:1). Allow to stand for at least 10 min to generate Sildenafil N-oxide, and then dilute with Mobile phase to 250 mL. Sample solution: 0.7 mg/mL of Sildenafil Citrate in Mobile phase 

Diluted sample solution: 1.4 µg/mL of Sildenafil citrate in Mobile phase from the Sample solution 

Sensitivity solution: 0.35 µg/mL of Sildenafil citrate in Mobile phase from the Diluted sample solution 

System suitability 

Samples: Diluted sample solution, Sensitivity solution, and System suitability solution 

[Note—The relative retention times for Sildenafil, Sildenafil N-oxide, and Sildenafil related compound A are about 1.0, 1.2, and 1.7, respectively.] 

Suitability requirements 

Resolution: NLT 2.5 between Sildenafil N-oxide and Sildenafil, System suitability solution 

Tailing factor: NMT 1.5 for the Sildenafil peak, Diluted sample solution 

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

Analysis 

Samples: Identification solution, Diluted sample solution, and Sample solution 

[Note—Identify Sildenafil related compound A from the Identification solution.] 

Calculate the percentage of Sildenafil related compound A and any other unspecified individual impurity in the portion of Sildenafil Citrate taken: 

Result = (r_U/r_S) × (C_S/C_U) × 100 

r_U = peak response of Sildenafil related compound A or any other unspecified impurity from the Sample solution 

r_S = peak response of Sildenafil from the Diluted sample solution

C_S = concentration of the Diluted sample solution (mg/mL) 

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

Acceptance criteria 

Sildenafil related compound A: NMT 0.3% 

Any other unspecified individual impurity: NMT 0.10% 

Total unspecified impurities: NMT 0.3% 

Total impurities: NMT 0.5%. Disregard any peak less than 0.05%. 

5 SPECIFIC TESTS 

Water Determination, Method I〈921〉: NMT 2.5% 

6 ADDITIONAL REQUIREMENTS 

Packaging and Storage: Preserve in air-tight containers, and store at room temperature. 

Change to read: 

USP Reference Standards 〈11〉 

USP Imidazole RS C₃H₄N₂ 68.08 

USP Sildenafil Citrate RS 

USP Sildenafil Related Compound A RS 

5-[2-Ethoxy-5-[(4-methylpiperazin-1-yl)sulfonyl]phenyl]-1-methyl-3-(2-methylpropyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; Also known as 1-{[3-(6,7-Dihydro-1-methyl-7-oxo-3-isobutyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl}-4-methylpiperazine. C₂₃H₃₂N₆O₄S 488.61