Itraconazole Capsules

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

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

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1 DEFINITION

Itraconazole Capsules contain NLT 90.0% and NMT 110.0% of the labeled amount of itraconazole (C₃₅H₃₈Cl₂N₈O₄).

2 IDENTIFICATION

A. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

B. The UV spectrum of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

3 ASSAY

Procedure

Solution A: 5.8 g/L of monobasic ammonium phosphate in water. Adjust with phosphoric acid to a pH of 2.0. Pass through a suitable filter of 0.45-μm pore size.

Solution B: Acetonitrile and tetrahydrofuran (90:10)

Mobile phase: Solution A and Solution B (45:55)

Diluent: Methanol and tetrahydrofuran (50:50)

Standard solution: 0.1 mg/mL of USP Itraconazole RS in Diluent. Sonicate, if necessary, to dissolve.

Sample stock solution: Nominally 1 mg/mL of itraconazole in Diluent prepared as follows. Transfer an amount nominally equivalent to 100 mg of itraconazole, from the contents of NLT 20 Capsules, to a 100-mL volumetric flask. Add 70 mL of Diluent, and sonicate for about 30 min. Dilute with Diluent to volume. Pass through a suitable filter of 0.45-μm pore size.

Sample solution: Nominally 0.1 mg/mL of itraconazole in Diluent from the Sample stock solution

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 225 nm. For Identi

cation B, use a diode array detector in the range of 200–400 nm.

Column: 4.6-mm × 15-cm; 3-μm packing L1

Column temperature: 30°

Flow rate: 1.5 mL/min

Injection volume: 10 μL

Run time: NLT 2 times the retention time of itraconazole

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 the labeled amount of itraconazole (C₃₅H₃₈Cl₂N₈O₄) in the portion of Capsules 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 = nominal concentration of itraconazole in the Sample solution (mg/mL)

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Change to read:

Dissolution 〈711〉

Test 1

Medium: 0.25% (w/v) sodium lauryl sulfate in 0.1 N hydrochloric acid; 900 mL

Apparatus 2: 75 rpm; with a three-prong sinker

Time: 45 min

Standard stock solution: 0.55 mg/mL of USP Itraconazole RS in 40% glacial acetic acid. Sonicate, if necessary, to dissolve.

Standard solution: 0.02 mg/mL of USP Itraconazole RS in Medium from the Standard stock solution

Sample solution: A filtered portion of the solution under test, suitably diluted with Medium, to obtain a concentration similar to that of the

Standard solution.

Blank: Medium

Instrumental conditions

Mode: UV

Analytical wavelength: 260 nm

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 2.0% for 5 replicates

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of itraconazole (C₃₅H₃₈Cl₂N₈O₄ ) released:

Result = (A_U/A_S)  x (C_S /L) × V × D × 100

A_U = absorbance of the Sample solution

A_S = absorbance of the Standard solution

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

L = label claim (mg/Capsule)

V = volume of Medium, 900 mL

D = dilution factor for the Sample solution, if applicable

Tolerances: NLT 80% (Q) of the labeled amount of itraconazole (C₃₅H₃₈Cl₂N₈O₄) is dissolved.

Test 2: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2. All solutions containing itraconazole should be stored in low-actinic or amber glassware and protected from light.

Medium: Simulated gastric

uid without enzymes, deaerated; 900 mL

Apparatus 2: 100 rpm; with a sinker, if necessary (USP 1-Aug-2021)

Time: 60 min

Quantify the amount of itraconazole dissolved by one of the following procedures.

Spectrophotometric procedure (USP 1-Aug-2021)

Standard stock solution: 0.55 mg/mL of USP Itraconazole RS in methanol prepared as follows. Transfer a suitable amount of USP

Itraconazole RS to a suitable volumetric flask and add about 80% of the flask volume of methanol. Heat the solution to 65° in a water bath, with intermittent stirring, until dissolved. Dilute with methanol to final volume.

Standard solution: 0.022 mg/mL of USP Itraconazole RS in Medium from the Standard stock solution

Sample solution: Pass a portion of the solution under test through a suitable filter and dilute with Medium, if necessary.

Blank: Medium

Instrumental conditions

Mode: UV

Analytical wavelength: 255 nm

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of itraconazole (C₃₅H₃₈Cl₂N₈O₄ ) dissolved:

Result = (A_U/A_S)  x (C_S /L) × V × D × 100

A_U = absorbance of the Sample solution

A_S = absorbance of the Standard solution

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

L = label claim (mg/Capsule)

V = volume of Medium, 900 mL

D = dilution factor for the Sample solution, if applicable

Chromatographic procedure

Buffer: 1 mL/L of triethylamine in water. Adjust with phosphoric acid to a pH of 2.5.

Mobile phase: Acetonitrile and Buffer (60:40)

Standard stock solution: 0.55 mg/mL of USP Itraconazole RS in acetonitrile. Sonicate, if necessary, to dissolve prior to final dilution.

Standard solution: 0.11 mg/mL of USP Itraconazole RS in Medium prepared from the Standard stock solution

Sample solution: Pass a portion of the solution under test through a suitable filter and dilute with Medium, if necessary.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 260 nm

Column: 4.6-mm x 15-cm; 5-μm packing L7

Column temperature: 30°

Flow rate: 1.2 mL/min

Injection volume: 10 μL

Run time: NLT 1.5 times the retention time of itraconazole

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 the labeled amount of itraconazole (C₃₅H₃₈Cl₂N₈O₄ ) dissolved:

Result = (r_U/r_S)  x (C_S /L) × V × D × 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)

L = label claim (mg/Capsule)

V = volume of Medium, 900 mL

D = dilution factor for the Sample solution, if applicable (USP 1-Aug-2021)

Tolerances: NLT 80% (Q) of the labeled amount of itraconazole (C₃₅H₃₈Cl₂N₈O₄) is dissolved.

Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

Organic Impurities

Solution A, Solution B, and Diluent: Prepare as directed in the Assay.

Mobile phase: See Table 1.

Table 1

System suitability solution: 5 mg/mL of USP Itraconazole System Suitability Mixture RS in Diluent. Sonicate, if necessary, to dissolve.

Standard solution: 0.025 mg/mL of USP Itraconazole RS in Diluent. Sonicate, if necessary, to dissolve.

Sample solution: Nominally 5 mg/mL of itraconazole in Diluent prepared as follows. Combine the contents of NLT 20 Capsules and transfer a portion nominally equivalent to 500 mg of itraconazole to a 100-mL flask. Add about 70 mL of Diluent and sonicate for 30 min with intermittent shaking. Dilute with Diluent to volume. Pass through a suitable filter of 0.45-μm pore size.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 225 nm

Column: 4.6-mm × 15-cm; 3-μm packing L1

Column temperature: 30°

Flow rate: 1.5 mL/min

Injection volume: 10 μL

System suitability

Samples: System suitability solution and Standard solution

[Note—See Table 2 for relative retention times.]

Suitability requirements

Resolution: NLT 1.5 between itraconazole and n-butyl isomer, System suitability solution

Tailing factor: NMT 2.0, Standard solution

Relative standard deviation: NMT 10.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of any individual impurity in the portion of Capsules taken:

Result = (r_U/r_S)  x (C_S/C_U ) × 100

r_U = peak response of any individual 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 = nominal concentration of itraconazole in the Sample solution (mg/mL)

Acceptance criteria: See Table 2.

Table 2

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

^b Process-related impurity included in the table for identification only. Process-related impurities are controlled in the drug substance and are not to be reported or included in the total impurities of the drug product.

^c 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-2,4-dihydro-3H-1,2,4-triazol-3-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- propyl-2,4-dihydro-3H-1,2,4-triazol-3-one.

^e 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-2,4-dihydro-3H-1,2,4-triazol-3-one.

^f 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-2,4-dihydro-3H-1,2,4-triazol-3-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-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one.

^h Mixture of 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)-2,4-dihydro-3H-1,2,4-triazol-3-one and 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- ({(2SR,4RS)-2-[(1H-1,2,4-triazol-1-yl)methyl]-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

6 ADDITIONAL REQUIREMENTS

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

Labeling: When more than one Dissolution test is given, the labeling states the Dissolution test used only if Test 1 is not used.

USP Reference Standards 〈11〉

USP Itraconazole RS

USP Itraconazole System Suitability Mixture RS

This is a mixture of itraconazole, 4-triazolyl isomer, propyl analog, epimer, n-butyl isomer, and didioxolanyl analog (other impurities may also be present).