Voriconazole

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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C₁₆H₁₄F₃N₅O          349.31

4-Pyrimidineethanol, α-(2,4-difluorophenyl)-5-fluoro-β-methyl-α-(1H-1,2,4-triazol-1-ylmethyl)-, (aR,βS);

(αR,βS)-α-(2,4-Difluorophenyl)-5-fluoro-β-methyl-α-(1H-1,2,4-triazol-1-ylmethyl)-4-pyrimidineethanol CAS RN^®: 137234-62-9; UNII: JFU09187TR.

1 DEFINITION

Voriconazole contains NLT 97.5% and NMT 102.0% of Voriconazole (C₁₆H₁₄F₃N₅O), calculated on the anhydrous and solvent-free basis.

2 IDENTIFICATION

Change to read:

A. ^▲SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197K_{▲(ERR 1-Oct-2020)}

B. The retention time of the major peak of the Sample solution corresponds to that of System suitability solution A, as obtained in the test for Voriconazole Related Compound B.

3 ASSAY

PROCEDURE

Buffer: 1.9 g/L of ammonium formate in water. Adjust with formic acid to a pH of 4.0.

Mobile phase: Acetonitrile, methanol, and Buffer (15:30:55)

Standard solution: 25 µg/mL of USP Voriconazole RS in Mobile phase. [NOTE-Sonicate to dissolve, if necessary.]

Sample solution: 25 µg/mL of Voriconazole in Mobile phase. [NOTE-Sonicate to dissolve, if necessary.]

Chromatographic system

(See Chromatography (621), System Suitability)

Mode: LC

Detector: UV 256 nm

Column: 3.9-mm x 15-cm; 4-µm packing L1

Column temperature: 35°

Flow rate: 1 mL/min

Injection size: 20 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Column efficiency: NLT 3500 theoretical plates

Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of voriconazole (C₁₆H₁₄F₃N₅O) in the portion of Voriconazole 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 Voriconazole RS in the Standard solution (µg/mL)

C_U = concentration of Voriconazole in the Sample solution (µg/mL)

Acceptance criteria: 97.5%-102.0% on the anhydrous and solvent-free basis

4 IMPURITIES

4.1 RESIDUE ON IGNITION (281)

NMT 0.1%

4.2 VORICONAZOLE RELATED COMPOUNDS C AND D

Mobile phase and Chromatographic system: Proceed as directed in the Assay.

System suitability solution: 0.25 µg/mL of USP Voriconazole RS in Mobile phase

Standard solution: 2.5 µg/mL each of USP Voriconazole RS, USP Voriconazole Related Compound C RS, and USP Voriconazole Related Compound D. RS in Mobile phase. [NOTE-Sonicate to dissolve, if necessary.]

Sample solution: 500 µg/mL of Voriconazole in Mobile phase. [NOTE-Sonicate to dissolve, if necessary.]

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Tailing factor: NMT 2.0 for the voriconazole peak, Standard solution

Column efficiency: NLT 3500 theoretical plates for the voriconazole peak, Standard solution

Relative standard deviation: NMT 10.0%, System suitability solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of voriconazole related compound C and voriconazole related compound D in the portion of Voriconazole taken:

                         Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of voriconazole related compound C or voriconazole related compound D from the Sample solution

r_S = peak response of voriconazole related compound C or voriconazole related compound D from the Standard solution

C_S = concentration of USP Voriconazole Related Compound C RS or USP Voriconazole Related Compound D RS in the Standard solution (µg/mL)

C_U = concentration of Voriconazole in the Sample solution (µg/mL)

Calculate the percentage of any unspecified impurity in the portion of Voriconazole taken:

                         Result = (r_U/r_S) × (C_S/C_U) × 100

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

r_S = peak response of voriconazole from the Standard solution 

C_S = concentration of USP Voriconazole RS in the Standard solution (µg/mL) 

C_U = concentration of Voriconazole in the Sample solution (µg/mL)

Acceptance criteria: See Table 1.

Table 1

^a 1-(2,4-Difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone.

^b (2RS,3SR)-2-(2,4-Difluorophenyl)-3-(pyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.

^c Disregard peaks less than 0.05%.

^d Include voriconazole related compound B and voriconazole related compound F.

4.3 VORICONAZOLE RELATED COMPOUND F

Sodium hydroxide solution: 470 g/L of sodium hydroxide in water

Mobile phase: Methanol, water, and Sodium hydroxide solution (500: 1500: 0.175). [NOTE-Minimize the carbonate formation in the Mobile phase by degassing methanol and water before mixing.]

Suppressant solution: 12 mM of sulfuric acid in water

Chloride stock solution: 85 µg/mL of sodium chloride in water

Standard stock solution: 250 µg/mL of USP Voriconazole Related Compound F RS. Dissolve in 50% of the final volume with methanol, and dilute with Mobile phase to volume.

Standard solution: 5 µg/mL of USP Voriconazole Related Compound FRS from the Standard stock solution in a mixture of methanol and Mobile phase (50:50)

System suitability solution A: 5 µg/mL of USP Voriconazole Related Compound FRS from the Standard stock solution and 1.7 µg/mL of sodium chloride in a mixture of methanol and Mobile phase (50:50)

System suitability solution B: 2.5 µg/mL of USP Voriconazole Related Compound F. RS from the Standard solution in Mobile phase

Sample solution: 5 mg/mL of Voriconazole. Dissolve in 50% of the final volume with methanol, and dilute with Mobile phase to volume.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: lon chromatography/LC

Detector: Conductivity with anion suppressor

Column: 4-mm x 5-cm guard column and 4-mm x 25-cm analytical column; both packing L46

Column temperature: 40°

Flow rate: 1 mL /min

Flow rate (for anion suppressor): 2 mL/min

Injection size: 20 µL

System suitability

Samples: System suitability solution A and System suitability solution B

[NOTE-The relative retention times for acetate ion (for information only), voriconazole related compound F, and chloride ion are 0.47, 1.0, and 1.5, respectively.]

Suitability requirements

Resolution: NLT 3.5 between the voriconazole related compound F and chloride peaks, System suitability solution A

Tailing factor: NMT 2.0, System suitability solution B

Relative standard deviation: NMT 10.0%, System suitability solution B

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of voriconazole related compound F in the portion of Voriconazole taken:

                         Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of voriconazole related compound F from the Sample solution

r_S = peak response of voriconazole related compound F from the Standard solution

C_S = concentration of USP Voriconazole Related Compound FRS in the Standard solution (µg/mL)

C_U = concentration of Voriconazole in the Sample solution (µg/mL)

Acceptance criteria: NMT 0.1%

4.4 VORICONAZOLE RELATED COMPOUND B

Initially dissolve the Standard and sample materials in 4% of the final volume of acetonitrile.

Buffer: 0.8 g/L of ammonium acetate. Adjust with glacial acetic acid to a pH of 5.0.

Mobile phase: Acetonitrile and Buffer (18:82)

System suitability solution A: 500 µg/mL of USP Voriconazole RS and 2.5 µg/mL of USP Voriconazole Related Compound B in Mobile phase.

System suitability solution B: 0.25 µg/mL of USP Voriconazole Related Compound B RS in Mobile phase

Standard solution: 2.5 µg/mL of USP Voriconazole Related Compound B RS in Mobile phase

Sample solution: 500 µg/mL of Voriconazole in Mobile phase.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 256 nm

Column: 4.6-mm x 25-cm; 5-µm packing L45

Column temperature: 30°

Flow rate: 1 mL/min

Injection size: 20 µL

System suitability

Samples: System suitability solution A and System suitability solution B

[NOTE-The relative retention times for voriconazole and voriconazole related compound B are 1.0 and 1.4, respectively.]

Suitability requirements

Resolution: NLT 4.0 between the voriconazole and voriconazole related compound B peaks, System suitability solution A

Tailing factor: NMT 2.0 for the voriconazole related compound B peak, System suitability solution A

Relative standard deviation: NMT 10.0%, System suitability solution B

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of voriconazole related compound B in the portion of Voriconazole taken:

                         Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of voriconazole related compound B from the Sample solution

r_S = peak response of voriconazole related compound B from the Standard solution

C_S = concentration of USP Voriconazole Related Compound B. RS in the Standard solution (µg/mL) 

C_U = concentration of Voriconazole in the Sample solution (µg/mL)

Acceptance criteria: NMT 0.2%

5 SPECIFIC TESTS

BACTERIAL ENDOTOXINS TEST (85): Where the label states that Voriconazole is sterile or that it must be subjected to further processing during the preparation of injectable dosage forms, it contains NMT 0.2 USP Endotoxin Units/mg of voriconazole.

STERILITY TESTS (71): Where the label states that Voriconazole is sterile, it meets the requirements.

WATER DETERMINATION, Method (921): NMT 0.4%

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in well-closed containers, and store at room temperature.

LABELING: Where it is intended for use in preparing injectable dosage forms, the label states that it is sterile or must be subjected to further processing during the preparation of injectable dosage forms.

USP REFERENCE STANDARDS (11)

USP Voriconazole RS

USP Voriconazole Related Compound B RS

(2S,3R)-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.

C₁₆H₁₄F₃N₅O          349.31

USP Voriconazole Related Compound C RS

1-(2,4-Difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone.

C₁₀H₇N₃OF₂             223.18

USP Voriconazole Related Compound D.RS

(2RS,3SR)-2-(2,4-Difluorophenyl)-3-(pyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.

C₁₆H₁₅F₂N₅O           331.32

USP Voriconazole Related Compound F.RS

((1RS,4SR)-7,7-Dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid.

C₁₀H₁₆O₄S                 232.30