Itraconazole

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

DOWNLOAD PDF HERE

C₃₅H₃₈Cl₂N₈O₄ 705.63

3H-1,2,4-Triazol-3-one, 4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-

piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-;

(±)-1-sec-Butyl-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]- Δ 2 -1,2,4-triazolin-5-one CAS RN®: 84625-61-6; UNII: 304NUG5GF4.

1 DEFINITION

Itraconazole contains NLT 98.0% and NMT 102.0% of itraconazole (C₃₅H₃₈Cl₂N₈O₄), calculated on the dried basis.

2 IDENTIFICATION

Change to read:

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K (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

Procedure

Prepare the solutions containing itraconazole immediately before use.

Solution A: 13.6 g/L of tetrabutylammonium hydrogen sulfate in water

Solution B: Acetonitrile

Diluent: Dilute 4.0 mL of hydrochloric acid with methanol to 1 L.

Mobile phase: See Table 1.

Table 1

Standard solution: 0.3 mg/mL of USP Itraconazole RS in Diluent

Sample solution: 0.3 mg/mL of Itraconazole 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

Column temperature: 30°

Flow rate: 1.5 mL/min

Injection volume: 10 μL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of itraconazole (C₃₅H₃₈Cl₂N₈O₄) in the portion of Itraconazole taken:

Result = (r_U/r_S)  x (C_S/C_U) × 100

r_U = peak response of itraconazole from the Sample solution

r_S = peak response of itraconazole from the Standard solution

C_S = concentration of USP Itraconazole RS in the Standard solution (mg/mL)

C_U = concentration of Itraconazole in the Sample solution (mg/mL)

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

4 IMPURITIES

Residue on Ignition 〈281〉

Sample: 1.0 g

Acceptance criteria: NMT 0.1%

Organic Impurities

Solution B, Diluent, and Chromatographic system: Proceed as directed in the Assay.

Solution A: 27.2 g/L of tetrabutylammonium hydrogen sulfate in water

Mobile phase: See Table 2.

Table 2

System suitability solution: 10 mg/mL of USP Itraconazole System Suitability Mixture RS in Diluent

Standard solution: 10.0 μg/mL of USP Itraconazole RS in Diluent

Sample solution: 10 mg/mL of Itraconazole in Diluent

System suitability

Sample: System suitability solution

Suitability requirements

Peak-to-valley ratio: NLT 1.5

Calculate the peak-to-valley ratio (p/v), using the following:

p/v = H_p/H_v

H_p = height above the baseline of the peak due to the n-butyl isomer impurity

H_v = height above the baseline of the lowest point of the curve separating this peak from the itraconazole peak

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Itraconazole taken:

Result = (r_U/r_S)  x (C_S/C_U) × 100

r_U = peak response of each impurity from the Sample solution

r_S = peak response of itraconazole from the Standard solution

C_S = concentration of USP Itraconazole RS in the Standard solution (mg/mL)

C_U = concentration of Itraconazole in the Sample solution (mg/mL)

Acceptance criteria: See Table 3. Disregard any peak less than 0.05%.

Table 3

^a 2-sec-Butyl-4-{4-[4-(4-methoxyphenyl)piperazin-1-yl]phenyl}-2H-1,2,4-triazol-3(4H)-one.

^b 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.

^c 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.

^d 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.

^e 4-(4-{4-[4-({(2RS,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.

^f 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.

^g 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-dioxolan-4-yl}methyl)-2H-1,2,4-triazol-3(4H)-one.

5 SPECIFIC TESTS

Optical Rotation 〈781A〉, Procedures, Angular Rotation

Sample: 100 mg/mL in methylene chloride. [Note—Use methylene chloride to zero the instrument.]

Acceptance criteria: −0.10° to +0.10° at 20°

Loss on Drying 〈731〉

Sample: Dry 1 g at 105° for 4 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight, light-resistant containers, and store at room temperature.

USP Reference Standards 〈11〉

USP Itraconazole RS

USP Itraconazole System Suitability Mixture RS

This mixture contains itraconazole and six other minor components (4-triazolyl isomer, propyl analog, isopropyl analog, epimer, n-butyl isomer, and didioxolanyl analog).