Clomiphene Citrate Tablets

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

Clomiphene Citrate Tablets contain NLT 93.0% and NMT 107.0% of the labeled amount of clomiphene citrate (C₂₆H₂₈ClNO·C₆H₈O₇).

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

3.1 Procedure

Use low-actinic glassware for all solutions.

Mobile phase: Methanol, water, and triethylamine (55:45:0.3). Adjust with phosphoric acid to a pH of 2.5.

System suitability solution: 0.002 mg/mL of USP Clomiphene Related Compound A RS and 0.05 mg/mL of USP Clomiphene Citrate RS in Mobile phase.

Standard solution: 0.05 mg/mL of USP Clomiphene Citrate RS in Mobile phase

Sample stock solution: Nominally 0.5 mg/mL of clomiphene citrate prepared in Mobile phase as follows. Transfer an equivalent of 50 mg of clomiphene citrate from finely powdered Tablets (NLT 20) to a 100-mL volumetric flask. Add about 50 mL of Mobile phase, and stir using a magnetic bar for 30 min. Remove the magnetic bar from the flask, dilute with Mobile phase to volume, and filter.

Sample solution: Nominally 0.05 mg/mL of clomiphene citrate prepared from the Sample stock solution in Mobile phase. Filter, and discard the first 10 mL.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 233 nm. For Identification B, use a diode array detector in the range of 190–400 nm.
• Column: 4.6-mm × 25-cm; 5-µm packing L26
• Flow rate: 1.0 mL/min
• Injection volume: 50 µL

System suitability

• Samples: System suitability solution and Standard solution
• [Note-The relative retention times for clomiphene related compound A, (Z)-isomer, and (E)-isomer are about 0.9, 1.0, and 1.2, respectively.]
• Suitability requirements
• Resolution: NLT 1.0 between clomiphene related compound A and (Z)-isomer; NLT 1.5 between (Z)-isomer and (E)-isomer, System suitability solution
• Column efficiency: NLT 2000 theoretical plates for the (E)-isomer, Standard solution
• Tailing factor: NMT 3.0 for the (E)-isomer, Standard solution
• Relative standard deviation: NMT 2.0% for both (E)- and (Z)-isomers, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of clomiphene citrate (C₂₆H₂₈ClNO·C₆H₈O₇) in the portion of Tablets taken:

Result = (r_u/r_s) × (C_s/C_u) × 100

r_u = sum of the peak responses of the (E)- and (Z)-isomers of clomiphene from the Sample solution

r_s = sum of the peak responses of the (E)- and (Z)-isomers of clomiphene from the Standard solution

C_s = concentration of USP Clomiphene Citrate RS in the Standard solution (mg/mL)

C_u = nominal concentration of clomiphene citrate in the Sample solution (mg/mL)

Acceptance criteria: 93.0%-107.0%

4 PERFORMANCE TESTS

4.1 Dissolution 〈711〉

Medium: Water; 900 mL

Apparatus 1: 100 rpm

Time: 30 min

Standard solution: USP Clomiphene Citrate RS in 0.1 N hydrochloric acid

Sample solution: Pass a portion of the solution under test through a suitable filter. Dilute with 0.1 N hydrochloric acid to a concentration similar to the Standard solution.

Instrumental conditions

• Mode: UV
• Analytical wavelength: 232 nm

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of clomiphene citrate (C₂₆H₂₈ClNO·C₆H₈O₇) dissolved:

Result = (A_u/A_s) × C_s × D × V × (1/L) × 100

A_u = absorbance of the Sample solution

A_s = absorbance of the Standard solution

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

D = dilution factor for the Sample solution

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

Tolerances: NLT 75% (Q) of the labeled amount of clomiphene citrate (C₂₆H₂₈ClNO·C₆H₈O₇) is dissolved.

4.2 Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

Change to read:

5.1 Organic Impurities

Use low-actinic glassware for all solutions.

Buffer: Acetonitrile, diethylamine, and water (40:0.8:60). Adjust with phosphoric acid to a pH of 6.2.

Solution A: Buffer and water (90:10)

Solution B: Buffer

Mobile phase: See Table 1.

System suitability stock solution: 0.28 mg/mL of USP Clomiphene Related Compound A RS in Buffer

System suitability solution: 1.25 mg/mL of USP Clomiphene Citrate RS and 0.028 mg/mL of USP Clomiphene Related Compound A RS, prepared as follows. Transfer 12.5 mg of USP Clomiphene Citrate RS into a 10-mL volumetric flask, add 1.0 mL of System suitability stock solution, and dilute with Buffer to volume.

Standard solution: 0.0125 mg/mL of USP Clomiphene Citrate RS in Buffer

Sample solution: Nominally 1.25 mg/mL of clomiphene citrate, prepared as follows. Transfer a suitable amount of clomiphene citrate from powdered Tablets (NLT 20) to a suitable volumetric flask. Add 50% of the flask volume of Buffer and shake for 30 min using a mechanical shaker. Dilute with Buffer to volume and pass through a suitable filter of 0.45-µm pore size, discarding the first 5 mL of filtrate.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 233 nm
• Column: 4.6-mm × 10-cm; 2.6-µm packing L7
• 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
• Peak-to-valley ratio: The ratio of the height of the clomiphene related compound A peak to the height of the valley between the clomiphene related compound A and clomiphene peaks is NLT 15, System suitability solution
• Relative standard deviation: NMT 5.0% from the sum of the peak areas of the (E)- and (Z)-isomers, Standard solution

Analysis

Samples: Standard solution and Sample solution

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

Result = (r_u/r_s) × (C_s/C_u) × (1/F) × 100

r_u = peak response of each impurity from the Sample solution

r_s = sum of the peak responses of the (E)- and (Z)-isomers of clomiphene from the Standard solution

C_s = concentration of USP Clomiphene Citrate RS in the Standard solution (mg/mL)

C_u = nominal concentration of clomiphene citrate in the Sample solution (mg/mL)

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2.

a {4-[2-(Diethylamino)ethoxy]phenyl}(phenyl)methanone.

b 2-{4-[2-(Diethylamino)ethoxy]phenyl}-1,2-diphenylethan-1-one.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers, protected from light, heat, and excessive humidity. Store at controlled room temperature.

USP Reference Standards 〈11〉

• USP Clomiphene Citrate RS
• USP Clomiphene Related Compound A RS

(E,Z)-2-[4-(1,2-Diphenylethenyl)phenoxy]-N,N-diethylethanamine hydrochloride.

C₂₆H₂₉NO·HCl 407.98