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Printed by: Dang Van Vu Official Date: Official as of 01-May-2020 Document Type: USP @2023 USPC
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IMPURITIES
Fluconazole
Change to read:
▲
▲ (USP 1-May-2019)

Change to read:

C13H12F2N6O 306.27 • ORGANIC IMPURITIES▲▲ (USP 1-May-2019)

1H-1,2,4-Triazole-1-ethanol, 1-(2,4-difluorophenyl)-1-(1H- Mobile phase: Acetonitrile and water (20:80)
1,2,4-triazol-1-ylmethyl)-; Standard solution: 10 µg/mL each of USP Fluconazole RS,
2,4-Difluoro-1′,1′-bis(1H-1,2,4-triazol-1-ylmethyl)benzyl USP Fluconazole Related Compound A RS, USP Fluconazole
alcohol CAS RN®: 86386-73-4. Related Compound B RS, and USP Fluconazole Related
Compound C RS, dissolved in acetonitrile, and then
DEFINITION diluted in Mobile phase
Fluconazole contains NLT 98.0% and NMT 102.0% of Sample solution: 3 mg/mL of Fluconazole in Mobile phase
fluconazole (C13H12F2N6O), calculated on the dried basis. Chromatographic system
IDENTIFICATION (See Chromatography á621ñ, System Suitability.)
Mode: LC
Change to read: Detector: UV 260 nm
Column: 4.6-mm × 15-cm; 3.5-µm packing L1
• A. ▲SPECTROSCOPIC IDENTIFICATION TESTS á197ñ, Infrared Column temperature: 40°
Spectroscopy: 197K▲ (CN 1-May-2020) Flow rate: 0.5 mL/min

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Injection volume: 20 µL
Change to read: System suitability
Sample: Standard solution
• B. ▲The retention time of the major peak of the Sample ▲
[NOTE— See Table 1 for relative retention
solution corresponds to that of the Standard solution, as times.]▲ (USP 1-May-2019)
obtained in the Assay.▲ (USP 1-May-2019)
ASSAY
Change to read:
ci Suitability requirements
Resolution: NLT 1.5 between fluconazole related
compound B and fluconazole related compound C
Relative standard deviation: NMT 5.0% for each peak
Analysis
• PROCEDURE Samples: Standard solution and Sample solution
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▲
Mobile phase: Acetonitrile and water (20:80) Calculate the percentage of fluconazole related compound
Standard solution: 0.5 mg/mL of USP Fluconazole RS in A, fluconazole related compound B, and fluconazole
Mobile phase related compound C in the portion of Fluconazole taken:
Sample solution: 0.5 mg/mL of Fluconazole in Mobile phase
Chromatographic system Result = (rU/rS) × (CS/CU) × 100
(See Chromatography á621ñ, System Suitability.)
O

Mode: LC rU = peak response of fluconazole related compound

Detector: UV 260 nm A, fluconazole related compound B, or
Column: 4.6-mm × 15-cm; 3-µm packing L1 fluconazole related compound C from the
Column temperature: 40° Sample solution
Flow rate: 0.5 mL/min rS = peak response of fluconazole related compound
Injection volume: 20 µL A, fluconazole related compound B, and
System suitability fluconazole related compound C from the
Sample: Standard solution Standard solution
Suitability requirements CS = concentration of USP Fluconazole Related
Tailing factor: NMT 2.0 Compound A RS, USP Fluconazole Related
Relative standard deviation: NMT 2.0% Compound B RS, and USP Fluconazole Related
Analysis Compound C RS in the Standard solution
Samples: Standard solution and Sample solution (mg/mL)
Calculate the percentage of fluconazole (C13H12F2N6O) in CU = concentration of Fluconazole in the Sample
the portion of Fluconazole taken: solution (mg/mL)

Result = (rU/rS) × (CS/CU) × 100 Calculate the percentage of any individual unspecified
impurity in the portion of Fluconazole taken:
rU = peak response of fluconazole from the Sample
solution Result = (rU/rS) × (CS/CU) × 100
rS = peak response of fluconazole from the Standard
solution rU = peak response of any individual impurity from the
CS = concentration of USP Fluconazole RS in the Sample solution
Standard solution (mg/mL) rS = peak response of fluconazole from the Standard
CU = concentration of Fluconazole in the Sample solution
solution (mg/mL)▲ (USP 1-May-2019) CS = concentration of USP Fluconazole RS in the
Standard solution (mg/mL)
Acceptance criteria: 98.0%–102.0% on the dried basis CU = concentration of Fluconazole in the Sample
solution (mg/mL)

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Printed by: Dang Van Vu Official Date: Official as of 01-May-2020 Document Type: USP @2023 USPC
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Acceptance criteria: See Table 1. Tailing factor: NMT 1.4 for the fluconazole peak, System
suitability solution
Table 1 Relative standard deviation: NMT 5.0%, Standard
Relative Acceptance solution
Retention Criteria, Analysis
Name Time NMT (%) Samples: Standard solution and Sample solution
Fluconazole related Calculate the percentage of each impurity in the portion of
compound A 0.5 0.2 Fluconazole taken:
Specified impurity 0.6 1.0 Result = (rU/rS) × (CS/CU) × (1/F) × 100
Fluconazole related
compound B 0.81 0.1 rU = peak response of each impurity from the Sample
Fluconazole related
solution
compound C 0.86 0.2 rS = peak response of fluconazole from the Standard
solution
Fluconazole 1.0 — CS = concentration of USP Fluconazole RS in the
Any individual unspeci- Standard solution (mg/mL)
—
fied impurity 0.1 CU = concentration of Fluconazole in the Sample
Total unknown impuri-
solution (mg/mL)
ties
—
0.3 F = relative response factor (see Table 3)
Total impurities — 1.5 Acceptance criteria: See Table 3.

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Table 3
Delete the following:
Relative Relative Acceptance
▲
• ORGANIC IMPURITIES, PROCEDURE 2 Retention Response Criteria,
Solution A: 0.01 M anhydrous sodium acetate solution. Name Time Factor NMT (%)
Adjust with 1 N acetic acid to a pH of 5.0, filter, and degas.
Solution B: Acetonitrile
Solution C: Methanol
Mobile phase: See Table 2.
ci Specified impurity

Specified impurity

Specified impurity
0.17—0.37

0.48—0.60

0.67—0.79
0.72

0.85

1.21
0.1

0.1

0.1

Specified impurity 1.14—1.18 0.96 0.1

Table 2
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Time Solution A Solution B Solution C Specified impurity 1.20—1.32 0.97 0.1
(min) (%) (%) (%)
Any unspecified
—
0 80 5 15 impurity 1.0 0.1

10 80 5 15 Total impurities — — 0.5

O

20 30 55 15
▲ (USP 1-May-2019)
23 30 55 15

25 80 5 15 Delete the following:

30 80 5 15 ▲
• ORGANIC IMPURITIES, PROCEDURE 3
Standard solution A: 1 mg/mL of USP Fluconazole RS in
Diluent: Methanol and Solution A (16:84) methanol (2.0%)
Standard solution: 0.01 mg/mL of USP Fluconazole RS in Standard solution B: 0.1 mg/mL of USP Fluconazole RS
Diluent from Standard solution A in methanol (0.2%)
System suitability solution: 0.02 mg/mL of USP Standard solution C: 0.05 mg/mL of USP Fluconazole RS
Fluconazole RS and 6 µg/mL of USP Desacetyl Diltiazem from Standard solution A in methanol (0.1%)
Hydrochloride RS in Diluent Sample solution: 50 mg/mL of Fluconazole in methanol
Sample solution: 2 mg/mL of Fluconazole in Diluent Chromatographic system
Chromatographic system (See Chromatography á621ñ, Thin-Layer Chromatography.)
(See Chromatography á621ñ, System Suitability.) Mode: TLC
Mode: LC Adsorbent: 0.25-mm layer of chromatographic silica gel
Detector: UV 261 nm mixture
Column: 4.0-mm × 10-cm; packing L1 Application volume: 10 µL
Flow rate: 1 mL/min Developing solvent system: Chloroform, methanol, and
Injection volume: 20 µL ammonium hydroxide (80:20:1)
System suitability Spray reagent A: 1.7 mg/mL of silver nitrate in water
Samples: Standard solution and System suitability solution Spray reagent B (potassium iodoplatinate solution):
[NOTE—The relative retention times for fluconazole and 375 mg of chloroplatinic acid in 5 mL of 1 N hydrochloric
desacetyl diltiazem are 1.0 and 1.2, respectively, acid. Dissolve 5 g of potassium iodide in 50 mL of water,
System suitability solution.] and store in a light-resistant container. Prepare a mixture
Suitability requirements of water, potassium iodide solution, and chloroplatinic
Resolution: NLT 10.0 between fluconazole and desacetyl acid solution (20:9:1).
diltiazem hydrochloride, System suitability solution Analysis
Column efficiency: NLT 30,000 theoretical plates for the Samples: Standard solution A, Standard solution B, Standard
fluconazole peak, System suitability solution solution C, and Sample solution

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Printed by: Dang Van Vu Official Date: Official as of 01-May-2020 Document Type: USP @2023 USPC
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Spray the dry plate with Spray reagent A, and expose the Acceptance criteria: The solution is clear and
plate to 365-nm UV light for 10–20 min. Dry the plate colorless.▲ (USP 1-May-2019)
for 20 min between 80° and 90°, then spray the plate
with Spray reagent B. Allow the plate to dry. Examine the ADDITIONAL REQUIREMENTS
plate and compare the intensities of any secondary spots • PACKAGING AND STORAGE: Preserve in tight containers, and
observed in the Sample solution with those of the store below 30°.
principal spots in the Standard solutions.
Acceptance criteria: No spot from the Sample solution with Delete the following:
an RF value between 0.10–0.25 and 0.27–0.41 is larger or ▲
• LABELING: If a procedure for Organic Impurities other than
more intense than that from Standard solution B Procedure 1 is used, then the labeling states with which
(0.2%). ▲ (USP 1-May-2019) Organic Impurities procedure(s) the article
• RESIDUE ON IGNITION á281ñ complies. ▲ (USP 1-May-2019)
Sample: 0.5 g
Acceptance criteria: NMT 0.1%
Change to read:
Delete the following: • USP REFERENCE STANDARDS á11ñ
▲
▲ (USP 1-May-2019)
▲
• IRON á241ñ USP Fluconazole RS
Sample solution: Transfer 0.5 g of the sample into a test USP Fluconazole Related Compound A RS
tube. Dissolve in 5 mL of alcohol, and add 5 mL of distilled 2-[2-Fluoro-4-(1H-1,2,4-triazol-1-yl)phenyl]-1,3-bis(1H-
water. 1,2,4-triazol-1-yl)-propan-2-ol.
Acceptance criteria: NMT 20 ppm▲ (USP 1-May-2019) ▲
C15H14FN9O 355.33▲ (USP 1-May-2019)

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SPECIFIC TESTS USP Fluconazole Related Compound B RS
• LOSS ON DRYING á731ñ 2-(4-Fluorophenyl)-1,3-di(1H-1,2,4-triazol-1-yl)-propan-
Analysis: Dry at 105° for 3 h. 2-ol.
Acceptance criteria: NMT 0.5% ▲
C13H13FN6O 288.28▲ (USP 1-May-2019)
ci USP Fluconazole Related Compound C RS
Delete the following: 1,1′-(1,3-Phenylene)di(1H-1,2,4-triazole).
▲
C10H8N6 212.21▲ (USP 1-May-2019)
▲
• CLARITY AND COLOR OF SOLUTION
Sample solution: Dissolve a sample in methanol to obtain a
5-in-100 solution (w/v).
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