You are on page 1of 2

JP XVII Official Monographs / Ketoconazole 1121

potassium bromide disk method under Infrared Spectropho-


tometry <2.25>, and compare the spectrum with the Refer- Ketoconazole
ence Spectrum: both spectra exhibit similar intensities of ab-
sorption at the same wave numbers. ケトコナゾール
(3) A solution of Ketamine Hydrochloride (1 in 10)
responds to the Qualitative Tests <1.09> (2) for chloride.
Absorbance <2.24> E 11zcm (269 nm): 22.0 – 24.5 (after dry-
ing, 30 mg, 0.1 mol/L hydrochloric acid TS, 100 mL).
pH <2.54> Dissolve 1.0 g of Ketamine Hydrochloride in 10
mL of freshly boiled and cooled water: the pH of the solu-
tion is between 3.5 and 4.5.
Purity (1) Clarity and color of solution—Dissolve 1.0 g of
Ketamine Hydrochloride in 5 mL of water: the solution is C26H28Cl2N4O4: 531.43
clear and colorless. 1-Acetyl-4-(4-{[(2RS,4SR )-2-(2,4-dichlorophenyl)-
(2) Heavy metals <1.07>—Proceed with 1.0 g of Keta- 2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-
mine Hydrochloride according to Method 1, and perform 4-yl]methoxy}phenyl)piperazine
the test. Prepare the control solution with 2.0 mL of Stand- [65277-42-1]
ard Lead Solution (not more than 20 ppm).
(3) Arsenic <1.11>—Prepare the test solution with 1.0 g Ketoconazole, when dried, contains not less than
of Ketamine Hydrochloride, according to Method 1, and 99.0z and not more than 101.0z of ketoconazole
perform the test (not more than 2 ppm). (C26H28Cl2N4O4).
(4) Related substances—Dissolve 0.5 g of Ketamine Hy-
Description Ketoconazole occurs as a white to light yellow-
drochloride in 10 mL of methanol and use this solution as
ish white powder.
the sample solution. Pipet 1 mL of the sample solution, add
It is soluble in methanol, sparingly soluble in ethanol
methanol to make exactly 200 mL, and use this solution as
(99.5), and practically insoluble in water.
the standard solution. Perform the test with these solutions
A solution of Ketoconazole in methanol (1 in 20) shows no
as directed under Thin-layer Chromatography <2.03>. Spot 2
optical rotation.
mL each of the sample solution and standard solution on a
plate of silica gel for thin-layer chromatography. Develop Identification (1) Determine the absorption spectrum of a
the plate with a mixture of cyclohexane and isopropylamine solution of Ketoconazole in methanol (3 in 100,000) as di-
(49:1) to a distance of about 10 cm, and air-dry the plate. rected under Ultraviolet-visible Spectrophotometry <2.24>,
Spray evenly Dragendorff's TS for spraying on the plate, dry and compare the spectrum with the Reference Spectrum:
the plate, and then spray evenly hydrogen peroxide TS: the both spectra exhibit similar intensities of absorption at the
spots other than the principal spot from the sample solution same wavelengths.
is not more intense than the spot from the standard solution. (2) Determine the infrared absorption spectrum of
Ketoconazole as directed in the potassium bromide disk
Loss on drying <2.41> Not more then 0.5z (1 g, 1059C,
method under Infrared Spectrophotometry <2.25>, and com-
3 hours).
pare the spectrum with the Reference Spectrum: both spectra
Residue on ignition <2.44> Not more than 0.1z (1 g). exhibit similar intensities of absorption at the same wave
numbers.
Assay Weigh accurately about 0.5 g of Ketamine Hydro-
(3) Perform the test with Ketoconazole as directed under
chloride, previously dried, dissolve in 1 mL of formic acid,
Flame Coloration Test <1.04> (2): a green color appears.
add 70 mL of a mixture of acetic anhydride and acetic acid
(100) (6:1), and titrate <2.50> with 0.1 mol/L perchloric acid Melting point <2.60> 148 – 1529C
VS (potentiometric titration). Perform a blank determina-
Purity (1) Heavy metals <1.07>—Proceed with 1.0 g of
tion, and make any necessary correction.
Ketoconazole according to Method 2, and perform the test.
Each mL of 0.1 mol/L perchloric acid VS Prepare the control solution with 1.0 mL of Standard Lead
= 27.42 mg of C13H16ClNO.HCl Solution (not more than 10 ppm).
(2) Related Substances—Dissolve 0.10 g of Ketoconazole
Containers and storage Containers—Tight containers.
in 10 mL of methanol, and use this solution as the sample so-
lution. Pipet 5 mL of the sample solution, and add methanol
to make exactly 100 mL. Pipet 1 mL of this solution, add
methanol to make exactly 10 mL, and use this solution as the
standard solution. Perform the test with exactly 10 mL each
of the sample solution and standard solution as directed
under Liquid Chromatography <2.01> according to the fol-
lowing conditions. Determine each peak area of both solu-
tions by the automatic integration method: the area of the
peak other than ketoconazole obtained from the sample so-
lution is not larger than 2/5 times the peak area of ketocona-
zole obtained from the standard solution, and the total area
of the peaks other than ketoconazole from the sample solu-
tion is not larger than the peak area of ketoconazole from
the standard solution.
1122 Ketoconazole Cream / Official Monographs JP XVII
Operating conditions— Identification To a quantity of Ketoconazole Cream,
Detector: An ultraviolet absorption photometer (wave- equivalent to 0.1 g of Ketoconazole, add 20 mL of 2-
length: 220 nm). propanol, shake for 20 minutes, centrifuge, and use the su-
Column: A stainless steel column 4.6 mm in inside diame- pernatant liquid as the sample solution. Separately, dissolve
ter and 10 cm in length, packed with octadecylsilanized silica 25 mg of ketoconazole in 5 mL of 2-propanol, and use this
gel for liquid chromatography (3 mm in particle diameter). solution as the standard solution. Perform the test with these
Column temperature: A constant temperature of about solutions as directed under Thin-layer Chromatography
259 C. <2.03>. Spot 5 mL each of the sample solution and standard
Mobile phase A: Acetonitrile for liquid chromatography. solution on a plate of silica gel with fluorescent indicator for
Mobile phase B: A solution of tetrabutylammonium thin-layer chromatography. Develop the plate with a mixture
hydrogensulfate (17 in 5000). of ethyl acetate, hexane, methanol, water and ammonia so-
Flowing of mobile phase: Control the gradient by mixing lution (28) (40:40:25:2:1) to a distance of about 12 cm, and
the mobile phases A and B as directed in the following table. air-dry the plate. Examine under ultraviolet light (main
wavelength: 254 nm): the principal spot obtained from the
Time after injection Mobile phase A Mobile phase B sample solution has the same R f value as the spot obtained
of sample (min) (volz) (volz) from the standard solution.
Assay Weigh accurately an amount of Ketoconazole
0 – 10 5 → 50 95 → 50
Cream, equivalent to about 25 mg of ketoconazole
10 – 15 50 50
(C26H28Cl2N4O4), dissolve in methanol to make exactly 100
mL. Pipet 10 mL of this solution, add exactly 4 mL of the
Flow rate: 2.0 mL per minute. internal standard solution, add methanol to make 50 mL,
Time span of measurement: For 15 minutes after injec- and use this solution as the sample solution. Separately,
tion, beginning after the solvent peak. weigh accurately about 25 mg of ketoconazole for assay,
System suitability— previously dried at 1059C for 4 hours, and dissolve in metha-
Test for required detectability: Pipet 2 mL of the standard nol to make exactly 50 mL. Pipet 5 mL of this solution, add
solution, and add methanol to make exactly 20 mL. Confirm exactly 4 mL of the internal standard solution, add methanol
that the peak area of ketoconazole obtained from 10 mL of to make 50 mL, and use this solution as the standard solu-
this solution is equivalent to 7 to 13z of that of ketocona- tion. Perform the test with 10 mL each of the sample solution
zole obtained from 10 mL of the standard solution. and standard solution as directed under Liquid Chromatog-
System performance: When the procedure is run with 10 raphy <2.01> according to the following conditions, and cal-
mL of the standard solution under the above operating con- culate the ratios, QT and QS, of the peak area of ketocona-
ditions, the number of theoretical plates and the symmetry zole to that of the internal standard.
factor of the peak of ketoconazole are not less than 40,000
and not more than 1.5, respectively. Amount (mg) of ketoconazole (C26H28Cl2N4O4)
System repeatability: When the test is repeated 6 times = MS × QT/QS
with 10 mL of the standard solution under the above operat- MS: Amount (mg) of ketoconazole for assay taken
ing conditions, the relative standard deviation of the peak
area of ketoconazole is not more than 2.5z. Internal standard solution—A solution of xanthone in meth-
anol (1 in 10,000).
Loss on drying <2.41> Not more than 0.5z (1 g, 1059C, Operating conditions—
4 hours). Detector: An ultraviolet absorption photometer (wave-
Residue on ignition <2.44> Not more than 0.1z (1 g). length: 230 nm).
Column: A stainless steel column 4.6 mm in inside diame-
Assay Weigh accurately about 0.2 g of Ketoconazole, pre- ter and 15 cm in length, packed with octadecylsilanized silica
viously dried, dissolve in 70 mL of a mixture of 2-butanone gel for liquid chromatography (5 mm in particle diameter).
and acetic acid (100) (7:1), and titrate <2.50> with 0.1 mol/L Column temperature: A constant temperature of about
perchloric acid VS (potentiometric titration). Perform a 409C.
blank determination in the same manner, and make any nec- Mobile phase: To ammonium acetate solution (1 in 200)
essary correction. add acetic acid (100) to adjust the pH to 5.0. To 250 mL of
Each mL of 0.1 mol/L perchloric acid VS this solution add 750 mL of methanol.
= 26.57 mg of C26H28Cl2N4O4 Flow rate: Adjust so that the retention time of ketocona-
zole is about 8 minutes.
Containers and storage Containers—Tight containers. System suitability—
Storage—Light-resistant. System performance: When the procedure is run with 10
mL of the standard solution under the above operating con-
ditions, the internal standard and ketoconazole are eluted in
Ketoconazole Cream this order with the resolution between these peaks being not
less than 5.
ケトコナゾールクリーム System repeatability: When the test is repeated 6 times
with 10 mL of the standard solution under the above operat-
Ketoconazole Cream contains not less than 95.0z ing conditions, the relative standard deviation of the ratio of
and not more than 105.0z of the labeled amount of the peak area of ketoconazole to that of the internal stand-
ketoconazole (C26H28Cl2N4O4: 531.43). ard is not more than 1.0z.

Method of preparation Prepare as directed under Creams, Containers and storage Containers—Tight containers.
with Ketoconazole.