Raltegravir Potassium

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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C₂₀H₂₀FKN₆O₅ 482.51 

4-Pyrimidinecarboxamide, N-[(4-uorophenyl)methyl]-1,6-dihydro-5-hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxadiazol-2- yl)carbonyl]amino]ethyl]-6-oxo-, monopotassium salt; 

Potassium 4-[(4-uorobenzyl)carbamoyl]-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1,6- dihydropyrimidin-5-olate CAS RN®: 871038-72-1. 

1 DEFINITION 

Raltegravir Potassium contains NLT 98.0% and NMT 102.0% of raltegravir potassium (C₂₀H₂₀FKN₆O₅), calculated on the anhydrous and solvent free basis. 

2 IDENTIFICATION 

Change to read: 

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

[Note—If the spectra obtained in the solid state show differences, dissolve the substance to be examined and the reference substance separately in methanol, evaporate to dryness, and record new spectra using the residues.] 

B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. C. 

Solution A: 100 g/L of sodium cobaltinitrite in water 

Sample solution: 40 mg/mL of Raltegravir Potassium in water 

Analysis: Combine 1 mL of Sample solution with 1 mL of dilute acetic acid and 1 mL of Solution A. 

Acceptance criteria: A yellow or orange yellow precipitate is formed immediately. 

3 ASSAY 

Procedure 

Diluent: Acetonitrile and water (25:75) 

Solution A: Phosphoric acid and water (1:1000) 

Solution B: Acetonitrile 

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

Table 1 

Standard solution: 0.1 mg/mL of USP Raltegravir Potassium RS in Diluent prepared as follows. Transfer a suitable amount of USP Raltegravir Potassium RS to a suitable volumetric flask and add about 40% of the flask volume of Diluent. Sonicate for 5 min, add the Diluent to about 90% of the nal volume, and allow to stand for 30 min. Dilute with Diluent to volume. 

Sample solution: 0.1 mg/mL of Raltegravir Potassium in Diluent prepared as follows. Transfer a suitable amount of the sample to a suitable volumetric flask and add about 40% of the flask volume of Diluent. Sonicate for 5 min, add the Diluent to about 90% of the nal volume, and allow to stand for 30 min. Dilute with Diluent to volume. 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 220 nm 

Column: 4.6-mm × 15-cm; 3.5-µm packing L11 

Column temperature: 15° 

Flow rate: 1 mL/min 

Injection volume: 10 µL 

System suitability 

Sample: Standard solution 

Suitability requirements 

Tailing factor: NMT 1.5 

Relative standard deviation: NMT 1.0% 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of raltegravir potassium (C₂₀H₂₀FKN₆O₅) in the portion of Raltegravir Potassium taken: 

Result = (r_U/r_S) × (C_S/C_U) × 100 

r_U = peak response of raltegravir from the Sample solution 

r_S = peak response of raltegravir from the Standard solution 

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

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

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

4 IMPURITIES 

Organic Impurities 

Diluent, Solution A, Solution B, Mobile phase, Sample solution, and Chromatographic system: Proceed as directed in the Assay. Peak identification solution: Prepare a solution containing 2 mg/mL of USP Raltegravir Potassium RS in 1 N sodium hydroxide solution. Stir the solution for 2 h at room temperature. Transfer 5 mL of this solution to a 50-mL volumetric flask and add 5 mL of 1 N hydrochloric acid. Dilute with Diluent to volume. [Note—In situ degradation generates raltegravir amine and raltegravir oxalylacetohydrazide analog.] System suitability solution: 0.1 mg/mL of USP Raltegravir Potassium RS and 0.2 µg/mL of USP Raltegravir Related Compound E RS in Diluent Standard stock solution: Use the Standard solution prepared in the Assay. 

Standard solution: 0.1 µg/mL of USP Raltegravir Potassium RS in Diluent from Standard stock solution 

System suitability 

Sample: System suitability solution 

[Note—See Table 2 for relative retention times.] 

Suitability requirements 

Resolution: NLT 1.5 between raltegravir related compound E and raltegravir 

Analysis 

Samples: Sample solution, Peak identification solution, and Standard solution 

Calculate the percentage of any individual impurity in the portion of Raltegravir Potassium taken: 

Result = (r_U/r_S) × (C_S/C_U) × 100 

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

r_S = peak response of raltegravir from the Standard solution 

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

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

Acceptance criteria: See Table 2. Reporting threshold is 0.05%. 

Table 2 

a 2-(2-Aminopropan-2-yl)-N-(4-uorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide. 

b(E)-2-(2-{[(Dimethylamino)methylidene]amino}propan-2-yl)-N-(4-uorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4- carboxamide. 

c 2-{2-[2-(2-Acetylhydrazinyl)-2-oxoacetamido]propan-2-yl}-N-(4-uorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4- carboxamide. 

d Ethyl (E)-N-{2-[(2-{4-[(4-uorobenzyl)carbamoyl]-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl}propan-2-yl)amino]-2- oxoacetyl}acetohydrazonate. 

e Ethyl (Z)-N-{2-[(2-{4-[(4-uorobenzyl)carbamoyl]-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl}propan-2-yl)amino]-2- oxoacetyl}acetohydrazonate. 

5 SPECIFIC TESTS 

Water Determination 〈921〉 

Sample: 0.5 g 

[Note—A mixture of equal volumes of methanol and formamide is suitable as solvent. Hydranal-Composite 2 is suitable as reagent.] Acceptance criteria: NMT 0.6% 

6 ADDITIONAL REQUIREMENTS 

Packaging and Storage: Preserve in tight containers. Store at controlled room temperature. 

USP Reference Standards 〈11〉 

USP Raltegravir Potassium RS 

USP Raltegravir Related Compound E RS 

N-{2-[4-(Benzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl]propan-2-yl}-5-methyl-1,3,4-oxadiazole-2-carboxamide. C₂₀H₂₂N₆O₅426.43