Fluconazole for Oral Suspension

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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DEFINITION

Fluconazole for Oral Suspension contains NLT 90.0% and NMT 110.0% of the labeled amount of fluconazole (C₁₃H₁₂F₂N₆O). It may contain a suitable preservative.

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.

1 ASSAY

Procedure

Diluted phosphoric acid: Phosphoric acid (1 in 10)

Buffer: 2.72 g/L of monobasic potassium phosphate, adjusted with Diluted phosphoric acid to a pH of 2.5

Mobile phase: Acetonitrile and Buffer (20:80)

Diluent: Methanol and water (50:50)

System suitability solution: 0.1 mg/mL of USP Fluconazole RS and 0.024 mg/mL of USP Sodium Benzoate RS in Diluent Standard solution: 0.1 mg/mL of USP Fluconazole RS in Diluent

Sample solution: Reconstitute the sample as directed on the label. Transfer an accurately weighed quantity of the suspension to a suitable volumetric ask to obtain a nominal concentration of 0.1 mg/mL of fluconazole. Sonicate in 70% of the ask volume of Diluent for 20 min with intermittent shaking. Dilute with Diluent to nal volume, mix, centrifuge, and pass through a suitable membrane filter.

1.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: 260 nm

Column: 4.6-mm × 15.0-cm; 5-µm packing L1

Flow rate: 1.5 mL/min

Injection volume: 50 µL

1.2 System suitability

Sample: System suitability solution

Suitability requirements

Resolution: NLT 5.0 between the fluconazole and benzoate peaks

Tailing factor: NMT 2.0 for the fluconazole peak

Relative standard deviation: NMT 2.0% for the fluconazole peak

1.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of fluconazole (C₁₃H₁₂F₂N₆O) in the portion of Fluconazole for Oral Suspension taken: 

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

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

C_S = concentration of the Standard solution

C_U = nominal concentration of the Sample solution

Acceptance criteria: 90.0%–110.0%

2 PERFORMANCE TESTS

Dissolution 〈711〉

2.1 Test 1

Medium: Water; 900 mL for 200 mg/5 mL suspension; 500 mL for 50 mg/5 mL suspension

Apparatus 2: 50 rpm

Time: 30 min

Standard stock solution: 1.1 mg/mL of USP Fluconazole RS in methanol

Standard solution

200 mg/5 mL suspension: 0.22 mg/mL of USP Fluconazole RS in Medium from the Standard stock solution

50 mg/5 mL suspension: 0.11 mg/mL of USP Fluconazole RS in Medium from the Standard stock solution

Sample solution: Reconstitute the suspension according to the label instructions. Weigh, and transfer an amount of the reconstituted suspension equivalent to 1 dose to the vessel. At the time specified withdraw 10 mL of the solution under test, and pass through a suitable filter of 0.45-µm pore size.

Mobile phase: Acetonitrile and water (20:80)

2.1.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 260 nm

Column: 4.6-mm × 15-cm; 5-µm packing L1

Column temperature: 40°

Flow rate: 1.5 mL/min

Injection volume: 50 µL

2.1.2 System suitability

Sample: Standard solution

Suitability requirements

Column efficiency: NLT 2000 theoretical plates

Tailing factor: NMT 2.0

Relative standard deviation: NMT 1.0%

2.1.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of fluconazole (C₁₃H₁₂F₂N₆O) dissolved (Q):

Result = (r_U /r_S ) × C_S × (V₁ /V₂ ) × (1/L) × 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

C_S = concentration of the Standard solution (mg/mL)

V₁ = volume of Medium (900 mL or 500 mL)

V₂ = volume of the reconstituted suspension in the Sample solution (mL). [Note—This is equivalent to the weight (g) of the reconstituted suspension in the Sample solution divided by the density of the reconstituted solution (g/mL).] L = label claim (mg/mL)

Tolerances: NLT 85% (Q) of the labeled amount of fluconazole (C₁₃H₁₂F₂N₆O) is dissolved.

2.2 Test 2

If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.

Medium: Water; 900 mL for 200 mg/5 mL suspension; 500 mL for 50 mg/5 mL suspension

Apparatus 2: 75 rpm

Time: 30 min

Mobile phase: Methanol and water (40:60). Adjust with glacial acetic acid to a pH of 3.4.

Standard solution: 0.055 mg/mL of USP Fluconazole RS and 0.025 mg/mL of USP Sodium Benzoate RS in Medium Sample solution: Reconstitute the suspension according to the label instructions. Weigh, and transfer an amount of the reconstituted suspension equivalent to one dose to the vessel. At the time specified withdraw an aliquot of the solution under test (5.0 mL for 50 mg/5 mL; 2.5 mL for 200 mg/5 mL), transfer to a 10-mL volumetric ask, and dilute with Medium to volume. Pass through a suitable filter of 0.45-µm pore size.

2.2.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 261 nm

Column: 4.6-mm × 15-cm; 5-µm packing L1

Column temperature: 30°

Flow rate: 1 mL/min

Injection volume: 40 µL

2.2.2 System suitability

Sample: Standard solution

Suitability requirements

Resolution: NLT 2.0 between fluconazole and sodium benzoate

Tailing factor: NMT 2.0 for the fluconazole peak

Relative standard deviation: NMT 2.0% for the fluconazole peak

2.2.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of fluconazole (C₁₃H₁₂F₂N₆O) dissolved (Q):

Result = (r_U /r_S ) × C_S × (V₁ /V₂ ) × (1/L) × 100

r_U = peak response of fluconazole from the Sample solution

r_S = peak response of fluconazole from the Standard solution

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

V₁ = volume of Medium (900 mL or 500 mL)

V₂ = volume of the reconstituted suspension in the Sample solution (mL). [Note—This is equivalent to the weight (g) of the

reconstituted suspension in the Sample solution divided by the density of the reconstituted solution (g/mL).]

L = label claim (mg/mL)

Tolerances: NLT 85% (Q) of the labeled amount of fluconazole (CC₁₃H₁₂F₂N₆O) is dissolved.

Deliverable Volume 〈698〉: Meets the requirements for oral suspension packaged in multiple-unit containers

3 IMPURITIES

Procedure

Solution A: 0.63 g/L of ammonium formate in water

Solution B: Acetonitrile

Mobile phase: See Table 1.

Table 1

Diluent: Acetonitrile and Solution A (13:87) 

System suitability solution: 0.3 mg/mL of USP Fluconazole RS, 3 µg/mL of USP Fluconazole Related Compound B RS, and 3 µg/mL of USP Fluconazole Related Compound C RS in Diluent. [Note—The use of sonication and stepwise dilutions may be appropriate.] Standard solution: 6 µg/mL of USP Fluconazole RS in Diluent. [Note—The use of sonication and stepwise dilutions may be appropriate.] Sample solution: Reconstitute the sample as directed on the label. Transfer an accurately weighed quantity of the suspension to a suitable volumetric ask to obtain a nominal concentration of 3 mg/mL of fluconazole. Sonicate in 40% of the ask volume of Diluent for 20 min with intermittent shaking. Dilute with Diluent to nal volume, mix, centrifuge, and pass through a suitable membrane filter.

3.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: 260 nm

Column: 4.6-mm × 12.5-cm; 3-µm packing L1

Column temperature: 40°

Flow rate: 1 mL/min

Injection volume: 20 µL

3.2 System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 1.5 between the fluconazole related compound B and fluconazole related compound C peaks and NLT 4.0 between the fluconazole related compound C and fluconazole peaks, System suitability solution

Tailing factor: NMT 2.0 for the fluconazole peak, System suitability solution

Relative standard deviation: NMT 5.0% for the fluconazole peak, Standard solution

3.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Fluconazole for Oral Suspension taken:

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

r_U = peak response of each impurity from the Sample solution

r_S = peak response of fluconazole from the Standard solution

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

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

Acceptance criteria: See Table 2.

Table 2

^a 2-[2-Fluoro-4-(1H-1,2,4-triazol-1-yl)phenyl]-1,3-bis(1H-1,2,4-triazol-1-yl)-propan-2-ol.

^b These are process impurities which are included in the table for identification only. These impurities are controlled in the drug substance. They are not to be reported for the drug product and should not be included in the total impurities.

^c 2-(2,4-Diuorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-(4H-1,2,4-triazol-4-yl)propan-2-ol.

4 SPECIFIC TESTS

Microbial Enumeration Tests 〈61〉andTests for Specified Microorganisms 〈62〉: The total aerobic microbial count does not exceed 102 cfu/g, and the total combined molds and yeasts count does not exceed 5 × 101 cfu/g. It meets the requirements of the test for absence of Escherichia coli.

pH 〈791〉: 3.0–5.0, in a suspension reconstituted as directed by the labeling

5 ADDITIONAL REQUIREMENTS

Packaging and Storage: Store dry powder below 30°. Store reconstituted suspension at 5°–30°, and protect from freezing.

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 Fluconazole RS

USP Fluconazole Related Compound B RS

2-(4-Fluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol.

C₁₃H₁₃FN₆O            288.28

USP Fluconazole Related Compound C RS

1,1′-(1,3-Phenylene)di(1H-1,2,4-triazole).

C₁₀H₈N₆                 212.21

USP Sodium Benzoate RS.