Raloxifene Hydrochloride

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

DOWNLOAD PDF HERE

C₂₈H₂₇NO₄S · HCl 510.04

Methanone, [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-, hydrochloride; 6-Hydroxy-2-(p-hydroxyphenyl)benzo[b]thien-3-yl-p-(2-piperidinoethoxy)phenyl ketone, hydrochloride CAS RN®: 82640-04-8; UNII:  4F86W47BR6.

1 DEFINITION

Raloxifene Hydrochloride contains NLT 97.5% and NMT 102.0% of raloxifene hydrochloride (C₂₈H₂₇NO₄S · HCl), calculated on the dried basis.

2 IDENTIFICATION

Change to read:

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

B. Identification Tests—General, Chloride〈191〉: It meets the requirements, the sample being dissolved in methanol.

3 ASSAY

Procedure

Buffer: Dissolve 7.2 g of monobasic potassium phosphate in 1000 mL of water. Add 1.5 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)

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

Standard solution: 0.05 mg/mL of USP Raloxifene Hydrochloride RS in Mobile phase

Sample solution: 0.05 mg/mL of Raloxifene Hydrochloride in Mobile phase

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

Sample: System suitability solution

Suitability requirements

Resolution: NLT 2.0 between raloxifene and raloxifene related compound C

Tailing factor: NMT 2.0 for raloxifene

Relative standard deviation: NMT 0.7% for raloxifene

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of raloxifene hydrochloride (C₂₈H₂₇NO₄S · HCl) in the portion of Raloxifene Hydrochloride 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 = concentration of the Sample solution (mg/mL)

Acceptance criteria: 97.5%–102.0% on the dried basis

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.1%

Organic Impurities

Solution A: Dissolve 9.0 g of monobasic potassium phosphate in 1000 mL of water. Add 0.6 mL of phosphoric acid, and further adjust with phosphoric acid or potassium hydroxide solution to a pH of 3.0 ± 0.1.

Solution B: Acetonitrile

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

Diluent A: Solution A and acetonitrile (70:30)

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 solution: 0.003 mg/mL of USP Raloxifene Hydrochloride RS in Diluent A

Sample solution: 3 mg/mL of Raloxifene Hydrochloride in Diluent A

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 raloxifene

Analysis

Samples: Standard solution and Sample solution

Record the chromatograms for NLT two 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 Raloxifene Hydrochloride taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of each impurity in the Sample solution

r_S = peak response of raloxifene in the Standard solution

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

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

Acceptance criteria: See Table 2. The reporting level for impurities is 0.05%.

Table 2

^a Methanone, [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3,7-diyl]bis[4-[2-(1-piperidinyl)ethoxy]phenyl].

5 SPECIFIC TESTS

Loss on Drying 〈731〉

Analysis: Dry a sample at 105° for 3 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers, and store at room temperature.

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