Clotrimazole

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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1 DEFINITION

Clotrimazole contains NLT 98.0% and NMT 102.0% of C₂₂H₁₇CIN₂, calculated on the dried basis.

2 IDENTIFICATION

Change to read:

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197M (CN 1-MAY-2020)

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

3.1 PROCEDURE

Buffer: 4.35 mg/mL of dibasic potassium phosphate

Mobile phase: Acetonitrile and Buffer (3:1). Pass through a membrane filter having a 0.2-µm or finer pore size. The ratio of volumes may be changed to obtain the required resolution.

Standard solution: 0.5 mg/mL of USP Clotrimazole RS in methanol

System suitability solution: 0.1 mg/mL each of USP Clotrimazole RS and USP Clotrimazole Related Compound A RS in methanol

Sample solution: 0.5 mg/mL of Clotrimazole in methanol

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm x 25-cm; 5-µm packing L1

Flow rate: 1.5 mL/min

Injection size: 25 µL

System suitability

Samples: Standard solution and System suitability solution

[NOTE-The relative retention times for clotrimazole and clotrimazole related compound A are 1.0 and 1.2, respectively.]

Suitability requirements

Resolution: NLT 2.0 between clotrimazole and clotrimazole related compound A, System suitability solution

Relative standard deviation: NMT 2.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of C₂₂H₁₇CIN₂, in the portion of Clotrimazole taken:

Result = (r_u/r_s) × (C_s/C_u) × 100

r_u = peak response of clotrimazole from the Sample solution

r_s = peak response of clotrimazole from the Standard solution

C_s = concentration of USP Clotrimazole RS in the Standard solution (mg/mL)

C_u = concentration of Clotrimazole in the Sample solution (mg/mL)

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

4 IMPURITIES

4.1 INORGANIC IMPURITIES

4.1.1 RESIDUE ON IGNITION (281): NMT 0.1%

4.2 ORGANIC IMPURITIES

4.2.1 PROCEDURE 1: LIMIT OF IMIDAZOLE

Adsorbent: 0.25-mm layer of chromatographic silica gel mixture

Standard solution: 500 µg/mL of USP Imidazole RS in chloroform

Sample solution: 100 mg/mL of Clotrimazole in chloroform

Application volume: 5 µL

Developing solvent system: Methanol and chloroform (3:2)

Analysis

Samples: Standard solution and Sample solution

Proceed as directed for Chromatography (621), Thin-Layer Chromatography. After air-drying the plate for 5 min, place it in a closed container with a dish containing 100 g of iodine in a shallow layer, and allow to remain for 60 min. Remove the plate from the container, and observe the chromatogram.

Acceptance criteria: Any brown spot from the Sample solution at an R, value corresponding to the principal spot from the Standard solution is not greater in size or intensity than the principal spot from the Standard solution: NMT 0.5% of imidazole.

4.2.2 PROCEDURE 2: LIMIT OF CLOTRIMAZOLE RELATED COMPOUND A

Buffer, Mobile phase, System suitability solution, and Chromatographic system: Proceed as directed in the Assay.

Standard solution: 50 µg/mL of USP Clotrimazole Related Compound A RS prepared by dissolving in methanol using about 75% of the final flask volume. Dilute with Buffer to volume.

Sample solution: Transfer 100 mg of Clotrimazole to a 10-mL volumetric flask, add 5 mL of methanol to dissolve, add 2.5 mL of Buffer, dilute with methanol to volume, and mix.

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of clotrimazole related compound A in the portion of Clotrimazole taken:

Result = (r_u/r_s) × (C_s/C_u) × 100

r_u= peak response of clotrimazole related compound A from the Sample solution

r_s = peak response of clotrimazole related compound A from the Standard solution

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

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

Acceptance criteria: NMT 0.5%

5 SPECIFIC TESTS

5.1 LOSS ON DRYING (731): Dry a sample at 105° for 2 h: it loses NMT 0.5% of its weight.

6 ADDITIONAL REQUIREMENTS

6.1 PACKAGING AND STORAGE: Preserve in tight containers.

6.2 USP REFERENCE STANDARDS (11)

USP Clotrimazole RS

USP Clotrimazole Related Compound A RS

(o-Chlorophenyl) diphenylmethanol.

C₁₉H₁₅CIO   294.78

USP Imidazole RS