Ketoconazole

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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C₂₆H₂₈Cl₂N₄O₄   531.43

Piperazine, 1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-, cis-;

(±)-cis-1-Acetyl-4-(p-[[2-(2,4-dichlorophenyl)-2-(imidazol-1- ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl)piperazine CAS RN®: 65277-42-1; UNII:

R9400W927I.

1 DEFINITION

Ketoconazole contains NLT 98.0% and NMT 102.0% of ketoconazole (C₂₆H₂₈Cl₂N₄O₄), calculated on the dried basis.

2 IDENTIFICATION

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

Change to read:

Procedure

Buffer: 3.4 mg/mL of tetrabutylammonium (ERR 1-Oct-2024) hydrogen sulfate in water

Solution A: Acetonitrile and Buffer (5:95)

Solution B: Acetonitrile and Buffer (50:50)

Mobile phase: See Table 1.

Table 1

Diluent: Methanol

Standard solution: 0.1 mg/mL of USP Ketoconazole RS in Diluent

Sample solution: 0.1 mg/mL of Ketoconazole in Diluent

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 225 nm

Column: 4.6-mm × 10-cm; 3-μm packing L1

Flow rate: 2.0 mL/min

Injection volume: 10 μL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 0.73%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of ketoconazole (C₂₆H₂₈Cl₂N₄O₄) in the portion of Ketoconazole taken:

Result = (r_U/r_S)x(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 Ketoconazole RS in the Standard solution (mg/mL)

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

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

4 IMPURITIES

Residue on Ignition 〈281〉

Sample: 2 g

Acceptance criteria: NMT 0.1%

Organic Impurities

Buffer, Solution A, Solution B, Mobile phase, Diluent, and Chromatographic system: Proceed as directed in the Assay.

Standard solution: 0.01 mg/mL each of USP Ketoconazole RS and USP Terconazole RS in Diluent

Sample solution 10.0 mg/mL of Ketoconazole in Diluent

System suitability

Sample: Standard solution

Suitability requirements

Resolution: NLT 2.0 between ketoconazole and terconazole peaks

Relative standard deviation: NMT 5.0% for the ketoconazole peak

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of any impurities in the portion of Ketoconazole taken:

Result = (r_U/r_S)x(C_S/C_U) × 100

r_U = peak response of any impurities from the Sample solution

r_S = peak response of Ketoconazole from the Standard solution

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

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

Acceptance criteria: Disregard any peak less than 0.05%.

Any individual unspecified impurity: NMT 0.10%

Total impurities: NMT 2.0%

5 SPECIFIC TESTS

Optical Rotation, Specific Rotation 〈781S〉

Sample solution: 40 mg/mL in methanol

Acceptance criteria: −1° to +1° at 20°

Loss on Drying 〈731〉

Analysis: Dry under vacuum at 80° for 4 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers.

USP Reference Standards 〈11〉

USP Ketoconazole RS

USP Terconazole RS

Piperazine, 1-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-(1-methylethyl)-, cis-;

cis-1-(p-{[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)-4-isopropylpiperazine.

C₂₆H₃₁Cl₂N₅O₃ 532.46