Ketoconazole Tablets

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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To view the Notice from the Expert Committee that posted in conjunction with this accelerated revision, please click www.uspnf.com/rb-notice-ketoconazole-tabs-20241122.

1 DEFINITION

Ketoconazole Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of ketoconazole (C₂₆H₂₈Cl₂N₄O₄).

IDENTIFICATION

A.

Standard solution: 1 mg/mL of USP Ketoconazole RS in chloroform

Sample solution: Nominally 1 mg/mL of ketoconazole in chloroform prepared as follows. Transfer a quantity of finely powdered Tablets, equivalent to 50 mg of ketoconazole, to a suitable flask. Add 50 mL of chloroform, shake for 2 min, and filter.

Chromatographic system

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

Mode: TLC

Adsorbent: 0.25-mm layer of chromatographic silica gel mixture

Application volume: 10 μL

Developing solvent system: n-Hexane, ethyl acetate, methanol, glacial acetic acid, and water (42:40:15:1:2)

Analysis: Allow the spots to dry, and develop the chromatogram in the Developing solvent system until the solvent front has moved three- fourths of the length of the plate. Remove the plate from the chamber, air-dry, and view under short-wavelength UV light.

Acceptance criteria: The R value of the principal spot of the Sample solution corresponds to that of the Standard solution.

2 ASSAY

Procedure

Solution A: Diisopropylamine in methanol (1 in 500)

Solution B: 5 mg/mL of ammonium acetate in water

Mobile phase: Solution A and Solution B (7:3)

Diluent: Methanol and methylene chloride (1:1)

Internal standard solution: 5 mg/mL of USP Terconazole RS in Diluent

Standard solution: 0.4 mg/mL of USP Ketoconazole RS in Diluent prepared as follows. Transfer 20 mg of USP Ketoconazole RS to a 50-mL volumetric flask. Add 5.0 mL of Internal standard solution, and dilute with Diluent.

Sample stock solution: Nominally 4 mg/mL of ketoconazole in Diluent prepared as follows. Weigh and finely powder NLT 20 Tablets. Transfer the nominal equivalent to 200 mg of ketoconazole to a suitable screw-capped bottle. Add 50.0 mL of Diluent, shake by mechanical means for 30 min, and centrifuge.

Sample solution: Nominally 0.4 mg/mL of ketoconazole in Diluent prepared as follows. Transfer 5.0 mL of the clear supernatant so obtained from the Sample stock solution to a 50-mL volumetric flask. Add 5.0 mL of Internal standard solution, and dilute with Diluent to volume.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 225 nm

Column: 3.9-mm × 30-cm; packing L1

Flow rate: 3 mL/min

Injection volume: 20 μL

System suitability

Sample: Standard solution

[Note—The relative retention times for ketoconazole and terconazole are 0.6 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 2.0 between ketoconazole and terconazole

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of ketoconazole (C₂₆H₂₈Cl₂N₄O₄) in the portion of Tablets taken:

Result = (R_U/R_S) × C_S/C_U) × 100

R_U = peak response ratio of ketoconazole to terconazole from the Sample solution

R_S = peak response ratio of ketoconazole to terconazole from the Standard solution

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

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

Acceptance criteria: 90.0%–110.0%

3 PERFORMANCE TESTS

Change to read:

Dissolution 〈711〉

Test 1 (RB 1-Dec-2024)

Medium: 0.1 N hydrochloric acid; 900 mL

Apparatus 2: 50 rpm

Time: 30 min

Analytical wavelength: UV 270 nm

Standard solution: USP Ketoconazole RS in Medium

Sample solutions: Pass portions of the solution under test through a suitable

filter of 0.45-μm pore size, and dilute with Medium to a

concentration similar to that of the Standard solution.

Tolerances: NLT 80% (Q) of the labeled amount of ketoconazole (C₂₆H₂₈Cl₂N₄O₄) is dissolved.

Test 2: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.

Medium: Simulated gastric fluid TS without pepsin; 800 mL

Apparatus 1: 100 rpm

Time: 15 min

Solution A: Add 2.0 mL of diisopropylamine to 1 L of methanol.

Solution B: Dissolve 5 g of ammonium acetate in 1 L of water.

Mobile phase: Solution A and Solution B (70:30)

Standard solution: 0.25 mg/mL of USP Ketoconazole RS in Medium. Sonicate to dissolve, if necessary.

Sample solution: Pass a portion of the solution under test through a suitable filter of 10-μm pore size.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 270 nm

Column: 3.9-mm × 30-cm; 10-μm packing L1

Flow rate: 1.5 mL/min

Injection volume: 20 μL

Run time: NLT 2 times the retention time of ketoconazole

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 3.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of ketoconazole (C₂₆H₂₈Cl₂N₄O₄) dissolved:

Result = (r_U/r_S) × C_S × V × (1/L) × 100

r_U = peak response of ketoconazole 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)

V = volume of Medium, 800 mL

L = label claim (mg/Tablet)

Tolerances: NLT 80% (Q) of the labeled amount of ketoconazole (C₂₆H₂₈Cl₂N₄O₄ ) is dissolved. (RB 1-Dec-2024)

Uniformity of Dosage Units 〈905〉: Meet the requirements

4 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers.

Add the following:

Labeling: The labeling states the Dissolution test used only if Test 1 is not used. (RB 1-Dec-2024)

USP Reference Standards 〈11〉

USP Ketoconazole RS

USP Terconazole RS