Clotrimazole
(kloe trim' a zole).
Click to View Image

C22H17ClN2 344.84
1H-Imidazole, 1-[(2-chlorophenyl)diphenylmethyl]-;    
1-(o-Chloro-,-diphenylbenzyl)imidazole     [23593-75-1].
DEFINITION
Clotrimazole contains NLT 98.0% and NMT 102.0% of C22H17ClN2, calculated on the dried basis.
IDENTIFICATION
•  B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.
ASSAY
•  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 
Mode:  LC
Detector:  UV 254 nm
Column:  4.6-mm × 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 C22H17ClN2 in the portion of Clotrimazole taken:
Result = (rU/rS) × (CS/CU) × 100
rU== peak response of clotrimazole from the Sample solution
rS== peak response of clotrimazole from the Standard solution
CS== concentration of USP Clotrimazole RS in the Standard solution (mg/mL)
CU== concentration of Clotrimazole in the Sample solution (mg/mL)
Acceptance criteria:  98.0%–102.0% on the dried basis
IMPURITIES
Inorganic Impurities 
•  Residue on Ignition 281: NMT 0.1%
•  Heavy Metals, Method II 231: NMT 10 ppm
Organic Impurities 
•  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 RF 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.
•  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 = (rU/rS) × (CS/CU) × 100
rU== peak response of clotrimazole related compound A from the Sample solution
rS== peak response of clotrimazole related compound A from the Standard solution
CS== concentration of the Standard solution (mg/mL)
CU== concentration of the Sample solution (mg/mL)
Acceptance criteria:  NMT 0.5%
SPECIFIC TESTS
•  Loss on Drying 731: Dry a sample at 105 for 2 h: it loses NMT 0.5% of its weight.
ADDITIONAL REQUIREMENTS
•  Packaging and Storage: Preserve in tight containers.
•  USP Reference Standards 11
USP Clotrimazole RS Click to View Structure
USP Clotrimazole Related Compound A RS
(o-Chlorophenyl)diphenylmethanol.
    C19H15ClO        294.78
USP Imidazole RS Click to View Structure
Auxiliary Information— Please check for your question in the FAQs before contacting USP.
Topic/Question Contact Expert Committee
Monograph Behnam Davani, Ph.D., M.B.A.
Senior Scientific Liaison
1-301-816-8394
(SM12010) Monographs - Small Molecules 1
Reference Standards RS Technical Services
1-301-816-8129
rstech@usp.org
USP35–NF30 Page 2740
Pharmacopeial Forum: Volume No. 35(6) Page 1449