Itraconazole CAS 84625-61-6 Assay 98.5~101.5%

Itraconazole contains not less than 98.5 percent and not more than 101.5 percent of C35H38Cl2N8O4, calculated on the dried basis.
Packaging and storage-Preserve in tight, light-resistant containers, and store at room temperature.
USP Reference standards <11>-
USP Itraconazole RS
USP Miconazole RS
Identification-
A: Infrared Absorption <197K>.
Angular rotation <781A>: between -0.10° and +0.10°, measured at 20°
Test solution: 100 mg per mL, in methylene chloride
Melting range <741>: between 166° and 170°
Loss on drying <731>-Dry about 1 g at 105° for 4 hours: it loses not more than 0.5% of its weight.
Residue on ignition <281>: not more than 0.1%, determined on 1.0 g.
Related compounds-
Solution A: 0.08 M tetrabutylammonium hydrogen sulfate.
Solution B: acetonitrile
Diluent-Prepare a mixture of methanol and tetrahydrofuran (1:1).
Standard solution-Dissolve an accurately weighed quantity of USP Itraconazole RS in Diluent, stepwise if necessar y, to obtain a solution having a known concentration of about 0.05 mg per mL.
Resolution solution-Dissolve suitable quantities of USP Itraconazole RS and USP Miconazole in RS in Diluent to obtain a solution having known concentrations of about 0.05 mg each per mL.
Test solution-Dissolve an accurately weighed quantity of Itraconazole in Diluent to obtain a solution having a known concentration of about 10 mg per mL.
Chromatographic system (see Chromatography <621>)-The liquid chromatograph is equipped with a 225-nm detector and a 4.6-mm × 10-cm column that contains 3- μm packing L1. The flow rate is about 1.5 mL per minute. The column temperature is maintained at 30 °. The chromatograph is programmed as follows
Time        Solution A     Solution B
(minutes) (%)                  (%)       Elution
0–20        80→50           20→50   linear gradient
20–25      50                  50 isocratic
25–30      80                  20 equilibration
[NOTE-Equilibrate the column for at least 30 minutes with acetonitrile at a flow rate of 1.5 mL per minute and then equilibrate at the initial eluent composition for at least 5 minutes.]
Chromatograph the Resolution solution, and record the peak responses as directed for Procedure: the resolution, R, between miconazole and itraconazole is not less than 2.0.
Procedure-Separately inject equal volumes (about 10 µL) of the Diluent, the Standard solution and the Test solution into the chromatograph and record the chromatograms. Calculate the percentage of each impurity in the portion of Itraconazole taken by the formula:
100(CS / CU)(rU / rS)
in which CS is the concentration, in mg per mL, of Itraconazole in the Standard solution; CU is the concentration, in mg per mL, of Itraconazole in the Test solution; rU is the peak area for each impurity in the Test solution; and rS is the peak area for Itraconazole in the Standard solution: not more than 0.5% of any specified impurity, as shown in Table 1, is found; and not more than 1.25% of total impurities is found. Disregard any peak observed in the Diluent and any peak less than 0.05%.
Table 1
Common Name Limit (%)
4-Methoxy derivative1 0.5
4-Triazolyl isomer2      0.5
Propyl analog3            0.5
Isopropyl analog4       0.5
Epimer5                      0.5
n-Butyl isomer6          0.5
Didioxolanyl analog7  0.5
1 2-sec-Butyl-4-{4-[4-(4-methoxyphenyl)piperazin-1-yl]phenyl}-2H-1,2,4-triazol-3(4H)-one.
2 4-(4-{4-[4-({(2RS,4SR)-2-[(4H-1,2,4-Triazol-4-yl)methyl]-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl}methoxy)phenyl]piperazin-1-yl}phenyl)-2-sec-butyl-2H-1,2,4-triazol-3(4H)-one.
3 4-(4-{4-[4-({(2RS,4SR)-2-[(1H-1,2,4-Triazol-1-yl)methyl]-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl}methoxy)phenyl]piperazin-1-yl}phenyl)-2-propyl-2H-1,2,4-triazol-3(4H)-one.
4 4-(4-{4-[4-({(2RS,4SR)-2-[(1H-1,2,4-Triazol-1-yl)methyl]-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl}methoxy)phenyl]piperazin-1-yl}phenyl)-2-isopropyl-2H-1,2,4-triazol-3(4H)-one.
5 4-(4-{4-[4-({(2 chelating agents. RS,4RS)-2-[(1H-1,2,4-Triazol-1-yl)methyl]-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl}methoxy)phenyl]piperazin-1-yl}phenyl)-2-sec-butyl-2H-1,2,4-triazol-3(4H)-one.
6 4-(4-{4-[4-({(2RS,4SR)-2-[(1H-1,2,4-Triazol-1-yl)methyl]-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl}methoxy)phenyl]piperazin-1-yl}phenyl)-2-butyl-2H-1,2,4-triazol-3(4H)-one.
7 4-(4-{4-[4-({(2RS,4SR)-2-[(1H-1,2,4-Triazol-1-yl)methyl]-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl}methoxy)phenyl]piperazin-1-yl}phenyl)-2-({(2RS,4SR)-2-[(1H-1,2,4-triazol-1-yl)methyl]-2-(2,4-dichlorophenyl)-1,3-dioxo-lan-4-yl}methyl)-2H-1,2,4-triazol-3(4H)-one.
Assay-
Diluent-Prepare a mixture of methyl ethyl ketone and glacial acetic acid (7:1).
Procedure-Dissolve about 0.3 g of Itraconazole, accurately weighed, in 70 ml of Diluent. Titrate with 0.1 M per chloric acid, determining the endpoint potentiometrically at the second inflection point. One mL of 0.1 M per chloric acid is equivalent to 35.3 mg of C 35H38Cl2N8O4.