Fluoxetine Delayed-Release Capsules
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This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition
Issued and maintained by the United States Pharmacopeial Convention (USP)
1 DEFINITION
Fluoxetine Delayed-Release Capsules contain an amount of Fluoxetine Hydrochloride equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of fluoxetine (C17H18F3NO).
2 IDENTIFICATION
Change to read:
A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197F (CN 1-May-2020)
Sample: Transfer the contents of 3 Capsules to a suitable container and grind to a fine powder. Transfer a portion of the powder, equivalent to 40 mg of fluoxetine, to another suitable container, and dissolve in 25 mL of 0.1 N hydrochloric acid. Pass the resulting solution through a suitable filter. Transfer 10 mL of the filtrate to a separatory funnel, add 20 mL of methylene chloride, and mix. Allow the phases to separate, and transfer the organic layer to a small glass container. Evaporate to dryness with the aid of a current of air and mild heat. Redissolve the residue with a few drops of methylene chloride, and transfer to a potassium bromide plate. Dry or evaporate to a thin film with the aid of a stream of nitrogen.
Acceptance criteria: Meet the requirements
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
3.1 Procedure
Solution A: Dissolve about 2.9 mL of glacial acetic acid and about 7.1 g of sodium 1-pentanesulfonate in 1 L of water. Adjust with 5 N sodium hydroxide to a pH of 5.0.
Mobile phase: Methanol and Solution A (67:33)
System suitability solution: 110 μg/mL of USP Fluoxetine Hydrochloride RS and 20 μg/mL of 4-trifluoromethylphenol in Mobile phase
Standard solution: 110 μg/mL of USP Fluoxetine Hydrochloride RS in Mobile phase
Sample stock solution: Nominally 0.2 mg/mL of fluoxetine from Capsules prepared as follows. Remove, as completely as possible, the contents of NLT 20 Capsules. Transfer a suitable portion of the contents to an appropriate volumetric flask and dissolve in 50% of the final flask volume of Mobile phase. Shake by mechanical means for 10 min and then sonicate for 5 min. Allow the solution to cool to room temperature and dilute with Mobile phase to volume.
Sample solution: Nominally 100 μg/mL of fluoxetine from Sample stock solution in Mobile phase. Pass through a suitable filter. Use the filtrate.
3.2 Chromatographic system
(See Chromatography 〈621〉, System Suitability.)
Mode: LC
Detector: UV 227 nm
Column: 4.6-mm × 7.5-cm; 3.5-μm packing L7
Column temperature: 38°
Flow rate: 1 mL/min
Injection volume: 10 μL
3.3 System suitability
Sample: System suitability solution
[Note- The relative retention times for 4-trifluoromethylphenol and fluoxetine are 0.7 and 1.0, respectively.]
3.4 Suitability requirements
Resolution: NLT 4.0 between 4-trifluoromethylphenol and fluoxetine
Tailing factor: NMT 1.7 for the fluoxetine peak
Relative standard deviation: NMT 2.0%
3.5 Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of the labeled amount of fluoxetine (C17H18F3NO) in the portion of Capsules taken:
Result = (rU/rS) × (CS/CU) × (Mr1/Mr2) × 100
rU = peak response from the Sample solution
rS = peak response from the Standard solution
CS = concentration of USP Fluoxetine Hydrochloride RS in the Standard solution (μg/mL)
CU = nominal concentration of fluoxetine in the Sample solution (μg/mL)
Mr1 = molecular weight of fluoxetine, 309.33
Mr2 = molecular weight of fluoxetine hydrochloride, 345.79
Acceptance criteria: 90.0%–110.0%
4 PERFORMANCE TESTS
4.1 Dissolution
Acid stage
Acid stage medium: 0.1 N hydrochloric acid; 250 mL, deaerated
Apparatus 3: 12 dips/min (dpm), using a polypropylene 40-mesh screen on the top and bottom of the reciprocating cylinder
Time: 2 h; Operate the apparatus for 2 h at 12 dpm, withdraw an aliquot of the Acid stage medium, and allow the apparatus to proceed to the Buffer stage.
Standard solution: 0.036 mg/mL of USP Fluoxetine Hydrochloride RS in Acid stage medium
Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-μm pore size. Use the filtrate.
4.1.1 Instrumental conditions
4.1.2 Mode: UV
Analytical wavelength: About 278 nm
4.1.3 Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of the labeled amount of fluoxetine (C17H18F3NO) dissolved:
Result = (AU/AS) × CS × (Mr1/Mr2) × V × (1/L) × 100
AU = minimum of the first derivative of the absorbance of the Sample solution
AS = minimum of the first derivative of the absorbance of the Standard solution
CS = concentration of USP Fluoxetine Hydrochloride RS in the Standard solution (mg/mL)
Mr1 = molecular weight of fluoxetine, 309.33
Mr2 = molecular weight of fluoxetine hydrochloride, 345.79
V = volume of Acid stage medium, 250 mL
L = label claim (mg/Capsule)
Tolerances: NMT 10% of the labeled amount of fluoxetine ((C17H18F3NO) is dissolved.
4.2 Buffer stage
Buffer stage medium: pH 6.8 phosphate buffer (prepared by mixing 3 L of 0.1 N hydrochloric acid and 1 L of 0.2 M tribasic sodium phosphate, and adjusting, if necessary, with 1 N hydrochloric acid or 1 N sodium hydroxide to a pH of 6.8 ± 0.05); 250 mL, deaerated
Apparatus 3: 12 dips/min (dpm), using a polypropylene 40-mesh screen on the top and bottom of the reciprocating cylinder
Time: 45 min; Operate the apparatus for 45 min at 12 dpm, and withdraw an aliquot of the Buffer stage medium.
Standard solution: 0.36 mg/mL of USP Fluoxetine Hydrochloride RS in Buffer stage medium
Sample solution: Pass a portion of the solution under test through a filter of 0.45-μm pore size. Use the filtrate.
4.2.1 Instrumental conditions
Mode: UV
Analytical wavelengths: Maximum absorbance at about 264 and 290 nm
4.2.2 Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of the labeled amount of fluoxetine (C17H18F3NO) dissolved:
Result = (AU/AS) × CS × (Mr1/Mr2) × V × (1/L) × 100
AU = absorbance at 264 nm − absorbance at 290 nm for the Sample solution
AS = absorbance at 264 nm − absorbance at 290 nm for the Standard solution
CS = concentration of USP Fluoxetine Hydrochloride RS in the Standard solution (mg/mL)
Mr1 = molecular weight of fluoxetine, 309.33
Mr2 = molecular weight of fluoxetine hydrochloride, 345.79
V = volume of Buffer stage medium, 250 mL
L = label claim (mg/Capsule)
Tolerances: NLT 75% (Q) of the labeled amount of fluoxetine (C17H18F3NO) is dissolved.
Uniformity of Dosage Units 〈905〉: Meet the requirements
5 IMPURITIES
5.1 Organic Impurities
Solution A: 6.5 g/L of sodium 1-octanesulfonate and 2.9 g/L of anhydrous sodium acetate in water adjusted with glacial acetic acid to a pH of 5.0
Mobile phase: Acetonitrile and Solution A (42:58)
Impurity identification solution A: 0.5 mg/mL of USP Fluoxetine Related Compound C RS in Mobile phase. [Note - The resulting solution contains 4-trifluoromethylphenol.]
Impurity identification solution B: Nominally 2.2 mg/mL of fluoxetine hydrochloride from USP Fluoxetine Hydrochloride RS prepared as follows. Transfer a suitable amount of USP Fluoxetine Hydrochloride RS to an appropriate volumetric flask and dilute with 1 N sulfuric acid to volume. Heat the flask to 85° for 3 h, and allow to cool to room temperature. [Note—The resulting solution contains aminomethyl-1-phenylpropanol, which is also known as 3-methylamino-1-phenylpropan-1-ol and α-[2-(methylamino)ethyl]benzenemethanol.]
System suitability stock solution: 0.135 mg/mL of USP Fluoxetine Hydrochloride RS, 0.01 mg/mL of USP Fluoxetine Related Compound C RS from Impurity identification solution A, and nominally 0.044 mg/mL of fluoxetine from Impurity identification solution B prepared as follows.
Transfer 13.5 mg of USP Fluoxetine Hydrochloride RS to a 100-mL volumetric flask and add 2 mL of Impurity identification solution A and 2 mL of Impurity identification solution B. Dilute with Mobile phase to volume.
System suitability solution: 5.4 μg/mL of USP Fluoxetine Hydrochloride RS and 0.4 μg/mL of USP Fluoxetine Related Compound C RS from System suitability stock solution in Mobile phase
Sensitivity solution: 0.43 μg/mL of USP Fluoxetine Hydrochloride RS from System suitability solution in Mobile phase
Sample solution: Nominally 0.4 mg/mL of fluoxetine from Capsules prepared as follows. Finely powder NLT 20 Capsules and transfer a suitable portion of the powder to an appropriate volumetric flask. Dissolve in and dilute with Mobile phase to volume. Pass the resulting solution through a suitable filter and use the filtrate.
5.2 Chromatographic system
(See Chromatography 〈621〉, System Suitability.)
Mode: LC
Detector: UV 215 nm
Column: 4.6-mm × 15-cm; 3.5-μm packing L7
Column temperature: 30°
Flow rate: 1 mL/min
Injection volume: 50 μL
Run time: NLT 3 times the retention time of fluoxetine
5.3 System suitability
Samples: System suitability solution and Sensitivity solution
[Note - The relative retention times for 4-trifluoromethylphenol, fluoxetine related compound C, and fluoxetine are 0.49, 0.70, and 1.0, respectively.]
5.4 Suitability requirements
Resolution: NLT 2.0 between 4-trifluoromethylphenol and fluoxetine related compound C; NLT 6.0 between fluoxetine related compound C and fluoxetine, System suitability solution
Signal-to-noise ratio: NLT 10 for fluoxetine, Sensitivity solution
5.5 Analysis
Sample: Sample solution
Calculate the percentage of each impurity in the portion of Capsules taken:
Result = (ri/rT) × 100
ri = peak response of each impurity from the Sample solution
rT = sum of all of the peak responses from the Sample solution
5.6 Acceptance criteria
Any individual impurity: NMT 0.2%
Total impurities: NMT 0.7%
6 ADDITIONAL REQUIREMENTS
Packaging and Storage: Preserve in tight containers, and store at controlled room temperature.
USP Reference Standards 〈11〉
USP Fluoxetine Hydrochloride RS
USP Fluoxetine Related Compound C RS
4-(Methyl{3-phenyl-3-[4-(trifluoromethyl)phenoxy]propyl}amino)-4-oxobutanoic acid; also known as N-Methyl-N-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]-succinamic acid.
C21H22F3NO4 409.40
