Raloxifene Hydrochloride 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

Raloxifene Hydrochloride Tablets contain NLT 93.0% and NMT 107.0% of the labeled amount of raloxifene hydrochloride (C₂₈H₂₇NO₄S · HCl).

2 IDENTIFICATION

Change to read:

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K 

Sample: Transfer a quantity of powdered Tablets, equivalent to 120 mg of raloxifene hydrochloride, to a suitable container. Add 20 mL of water, and shake to form a uniform slurry. Centrifuge, and discard the supernatant. Add 5 mL of isopropyl alcohol, shake to form a slurry, filter, and rinse the residue with isopropyl alcohol. Dry the residue at 105° for 30 min. Alternatively, add 40 mL of water to the powdered Tablets and vortex to form a uniform slurry. Centrifuge, and discard the supernatant. Repeat the washing process. Add 40 mL of methanol to the residue, vortex to form a uniform slurry, and centrifuge. Transfer the clear liquid to an appropriate container and evaporate to dryness.

Analysis: Prepare a potassium bromide dispersion with the Sample. Similarly prepare the Standard, starting with a slurry containing 12 mg/mL of USP Raloxifene Hydrochloride RS in water.

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

Procedure

Buffer: Dissolve 7.2 g of monobasic potassium phosphate in 1000 mL of water. Add 1.3 mL of phosphoric acid, and further adjust with phosphoric acid or potassium hydroxide solution to a pH of 2.5 ± 0.1.

Mobile phase: Acetonitrile and Buffer (33:67)

Diluent: Acetonitrile and Buffer (60:40)

System suitability solution: Prepare as directed in the test for Organic Impurities.

Standard solution: 0.06 mg/mL of USP Raloxifene Hydrochloride RS in Diluent

Sample solution: Transfer a sufficient quantity of Tablets to a volumetric flask of suitable size, add Diluent, and shake to disintegrate the Tablets. Sonicate if necessary. Dilute with Diluent to obtain a solution having a concentration of 0.06 mg/mL of raloxifene hydrochloride, based on the label claim. Filter, and use the clear solution.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 280 nm

Column: 4.6-mm × 15-cm; 3.5-µm base-deactivated packing L7

Column temperature: 35°

Flow rate: 1.5 mL/min

Injection volume: 10 µL

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 2.0 between raloxifene and raloxifene related compound C, System suitability solution

Tailing factor: NMT 2.0 for raloxifene, System suitability solution

Relative standard deviation: NMT 1.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of raloxifene hydrochloride (C₂₈H₂₇NO₄S · HCl) in the portion of Tablets 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 USP Raloxifene Hydrochloride RS in the Standard solution (mg/mL)

C_U = nominal concentration of raloxifene hydrochloride from the Sample solution (mg/mL)

Acceptance criteria: 93.0%–107.0%

4 PERFORMANCE TESTS

Dissolution 〈711〉

Test 1

Medium: 0.1% polysorbate 80; 1000 mL

Apparatus 2: 50 rpm

Time: 30 min

Mobile phase: Acetonitrile, water, and triethylamine (500:500:2). Adjust with phosphoric acid to a pH of 4.0.

Triethylamine phosphate suspension: Add 2.0 mL of triethylamine to 500 mL of acetonitrile, and adjust with phosphoric acid to a pH of 4.0. [Note—Triethylamine phosphate will precipitate; keep the suspension well mixed.]

Standard solution: Prepare a solution having a known concentration equivalent to the expected concentration of the Sample solution by dissolving USP Raloxifene Hydrochloride RS in a small volume (NMT 10% of the nal volume) of methanol. Dilute with Medium to volume, and mix the resulting solution with Triethylamine phosphate suspension (1:1).

Sample solution: Pass a portion of the solution under test through an appropriate filter of 0.45-µm pore size. Mix the resulting solution and Triethylamine phosphate suspension (1:1).

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 290 nm

Column: 4.6-mm × 15-cm; 3.5-µm base-deactivated packing L10. If the analyte peak splits, use a guard column containing packing L3. Flow rate: 2 mL/min

Injection volume: 50 µL

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Determine the percentage of the labeled amount of raloxifene hydrochloride (C₂₈H₂₇NO₄S · HCl) dissolved:

Result = (r_U/r_S)× (C_S/L) × F × 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

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

L = label claim (mg/Tablet)

F = volume of Medium, 1000 mL

Tolerances: NLT 80% (Q) of the labeled amount of raloxifene hydrochloride is dissolved.

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

Medium: 1% sodium dodecyl sulfate in 0.05 M phosphate buffer prepared as follows. 1.7 g/L of sodium hydroxide and 7 g/L of monobasic sodium phosphate monohydrate. Adjust to a pH of 7.5, if necessary. Add 10 g of sodium dodecyl sulfate per L; 900 mL. Apparatus 2: 75 rpm

Time: 45 min

Buffer: 2.8 g/L of sodium dodecyl sulfate. Adjust with glacial acetic acid to a pH of 4.0.

Diluent: Acetonitrile and water (50:50)

Mobile phase: Acetonitrile and Buffer (55:45)

Standard stock solution: 0.48 mg/mL of USP Raloxifene Hydrochloride RS in Diluent

Standard solution: 0.072 mg/mL of USP Raloxifene Hydrochloride RS in Medium from the Standard stock solution Sample solution: Pass a portion of the solution under test through a suitable filter.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 286 nm

Column: 3.9-mm × 15-cm; 5-µm packing L1

Column temperature: 30°

Flow rate: 1 mL/min

Injection volume: 10 µL

Run time: NLT 1.3 times the retention time of raloxifene

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 raloxifene hydrochloride (C₂₈H₂₇NO₄S · HCl) dissolved

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

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

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

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

Tolerances: NLT 80% (Q) of the labeled amount of raloxifene hydrochloride (C₂₈H₂₇NO₄S · HCl) is dissolved.

Test 3: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3. Medium: pH 2.2 phosphate buffer prepared as follows. Dissolve 3.7 g of monobasic potassium phosphate in 1 L of water. Adjust with phosphoric acid to a pH of 2.2; 1000 mL.

Apparatus 2: 50 rpm

Time: 20 min

Mobile phase: Acetonitrile, water, and triethylamine (400:600:2). Adjust with diluted phosphoric acid to a pH of 4.0. Standard stock solution: 0.30 mg/mL of USP Raloxifene Hydrochloride RS prepared as follows. Transfer an appropriate amount of USP Raloxifene Hydrochloride RS to a suitable volumetric flask and add 50% of the flask volume of methanol. Sonicate for 20 min with occasional shaking and then dilute with Medium to volume.

Standard solution: 0.06 mg/mL of USP Raloxifene Hydrochloride RS in Medium from the Standard stock solution Sample solution: Centrifuge a portion of the solution under test and use the clear supernatant. [Note—The use of a centrifuge speed of 2000 rpm for 10 min may be suitable.]

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 290 nm

Column: 4.6-mm × 25-cm; 5-µm packing L1

Flow rate: 1 mL/min

Injection volume: 10 µL

Run time: NLT 1.7 times the retention time of raloxifene

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of raloxifene hydrochloride (C₂₈H₂₇NO₄S · HCl) dissolved: 

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

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

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

V = volume of Medium, 1000 mL

L = label claim (mg/Tablet)

Tolerances: NLT 80% (Q) of the labeled amount of raloxifene hydrochloride (C₂₈H₂₇NO₄S · HCl) is dissolved.

Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

Organic Impurities

Buffer: Dissolve 9.0 g of monobasic potassium phosphate in 1000 mL of water. Add 0.5 mL of phosphoric acid, and further adjust with phosphoric acid or potassium hydroxide solution to a pH of 3.0 ± 0.1.

Solution A: Buffer and acetonitrile (75:25)

Solution B: Buffer and acetonitrile (50:50)

Mobile phase: See Table 1. Adjust the start time of the gradient step on the basis of the instrument's dwell volume. Table 1

Diluent A: Acetonitrile and Buffer (60:40)

Diluent B: Tetrahydrofuran and methanol (70:30)

Raloxifene related compound C solution: 0.15 mg/mL of USP Raloxifene Related Compound C RS in Diluent B System suitability solution: Transfer 15 mg of USP Raloxifene Hydrochloride RS to a 50-mL volumetric flask, add 1.0 mL of Raloxifene related compound C solution, and dilute with Diluent A to volume.

Standard stock solution: 0.06 mg/mL of USP Raloxifene Hydrochloride RS in Diluent A

Standard solution: Mix 5 mL of the Standard stock solution and 45 mL of Diluent A, and dilute with Solution A to 100.0 mL (0.003 mg/mL). Sample solution: Transfer a sufficient quantity of Tablets to a volumetric flask of a suitable size to obtain a solution of raloxifene hydrochloride having a concentration of 6 mg/mL, based on the label claim. Add Diluent A, and shake to disintegrate the Tablets. Sonicate, if necessary, and add Diluent A to volume. Transfer 5 mL of this solution to a 10-mL volumetric flask, and dilute with Solution A to volume to obtain a solution having a concentration of 3 mg/mL of raloxifene hydrochloride, based on the label claim. Filter, and use the clear solution.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 280 nm

Column: 4.6-mm × 25-cm; 5-µm base-deactivated packing L7

Column temperature: 35°

Flow rate: 1 mL/min

Injection volume: 10 µL

System suitability

Sample: System suitability solution

Suitability requirements

Resolution: NLT 3.0 between raloxifene and raloxifene related compound C

Tailing factor: NMT 2.0 for the raloxifene peak

Analysis

Samples: Standard solution and Sample solution

Record the chromatograms for NLT 2 times the retention time of the raloxifene peak, and measure all of the peak responses. Calculate the percentage of each impurity in the portion of Tablets 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 USP Raloxifene Hydrochloride RS in the Standard solution (mg/mL)

C_U = nominal concentration of raloxifene hydrochloride from the Sample solution (mg/mL)

Acceptance criteria: See Table 2.

Table 2

a 1-(2-{4-[6-Hydroxy-2-(4-hydroxyphenyl)benzothiophene-3-carbonyl]phenoxy}ethyl)piperidine 1-oxide.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers, and store at controlled room temperature.

Labeling: When more than one Dissolution test is given, the labeling states the test used only if Test 1 is not used. USP Reference Standards 〈11〉

USP Raloxifene Hydrochloride RS

USP Raloxifene Related Compound C RS

1-(2-{4-[6-Hydroxy-2-(4-hydroxyphenyl)benzothiophene-3-carbonyl]phenoxy}ethyl)piperidine 1-oxide monohydrate. C₂₈H₂₇NO₅S. H₂O 507.60