Ketoconazole
(kee'' toe kon' a zole).
Click to View Image

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     [65277-42-1].
DEFINITION
Ketoconazole contains NLT 98.0% and NMT 102.0% of ketoconazole (C26H28Cl2N4O4), calculated on the dried basis.
IDENTIFICATION
Add the following:
•   B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.2S (USP38)
ASSAY
Change to read:
•  Procedure
Buffer:  3.4 mg/mL of tetrabutyl ammonium 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
Time
(min) 		Solution A
(%) 		Solution B
(%)
0 100 0
20 0 100
25 0 100
26 100 0
30 100 0
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 = (rU/rS) × (CS/CU) × 100

rU == peak response from the Sample solution
rS == peak response from the Standard solution
CS == concentration of USP Ketoconazole RS in the Standard solution (mg/mL)
CU == concentration of Ketoconazole in the Sample solution (mg/mL)
Acceptance criteria:  98.0%–102.0% on the dried basis2S (USP38)
IMPURITIES
•  Residue on Ignition 281
Sample:  2 g
Acceptance criteria:  NMT 0.1%
Delete the following:
•  Heavy Metals, Method II 231: NMT 20 ppm(Official 1-Dec-2015)
Change to read:
•  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 = (rU/rS) × (CS/CU) × 100

rU == peak response of any impurities from the Sample solution
rS == peak response of Ketoconazole from the Standard solution
CS == concentration of USP Ketoconazole RS in the Standard solution (mg/mL)
CU == 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%2S (USP38)
SPECIFIC TESTS
Delete the following:
•  Melting Range or Temperature 741: 148–1522S (USP38)
•  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%
ADDITIONAL REQUIREMENTS
•  Packaging and Storage: Preserve in well-closed containers.
Change to read:
•  USP Reference Standards 11
USP Ketoconazole RS Click to View Structure
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 2S (USP38)
Auxiliary Information— Please check for your question in the FAQs before contacting USP.
Topic/Question Contact Expert Committee
Monograph Shankari Shivaprasad, Ph.D.
Scientific Liaison
(301) 230-7426		 (SM12010) Monographs - Small Molecules 1
Reference Standards RS Technical Services
1-301-816-8129
rstech@usp.org
USP38–NF33 Page 4005
USP38–NF33 Supplement : No. 2 Page 8127
Pharmacopeial Forum: Volume No. 40(4)