Raloxifene Hydrochloride Tablets
DEFINITION
Raloxifene Hydrochloride Tablets contain NLT 93.0% and NMT 107.0% of the labeled amount of raloxifene hydrochloride (C28H27NO4S·HCl).
IDENTIFICATION
• A. Infrared Absorption 
197K
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.
for 30 min.
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.
• B.
The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.
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 stock solution:
Prepare as directed under 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
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 size:
10 µL
System suitability
Samples:
System suitability stock solution and Standard solution
Suitability requirements
Resolution:
NLT 2.0 between raloxifene and raloxifene N-oxide, System suitability stock solution
Tailing factor:
NMT 2.0 for raloxifene, System suitability stock 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 in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response from the Sample solution |
| rS | = | = peak response from the Standard solution |
| CS | = | = concentration of USP Raloxifene Hydrochloride RS in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of the Sample solution (mg/mL) |
Acceptance criteria:
93.0%–107.0%
PERFORMANCE TESTS
• Dissolution 711
711
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 final 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
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 size:
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 raloxifene hydrochloride dissolved:
Result = (rU/rS) × (CS/L) × F × 100
| rU | = | = peak response from the Sample solution |
| rS | = | = peak response from the Standard solution |
| CS | = | = concentration of raloxifene hydrochloride 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.
• Uniformity of Dosage Units 905:
Meet the requirements
905:
Meet the requirements
IMPURITIES
Organic Impurities
• Procedure
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
Table 1
| Time (min) |
Solution A (%) |
Solution B (%) |
|---|---|---|
| 0.00 | 100 | 0 |
| 5.00 | 100 | 0 |
| 36.25 | 0 | 100 |
| 38.25 | 100 | 0 |
| 48.00 | 100 | 0 |
[Note—Adjust the start time of the gradient step on the basis of the instrument's dwell volume. ]
Diluent:
Acetonitrile and Buffer (60:40)
System suitability stock solution:
Transfer 6 mg of USP Raloxifene Hydrochloride RS to a 50-mL volumetric flask, and add 15.0 mL of acetonitrile, 3.0 mL of water, and 5.0 mL of 30% hydrogen peroxide (unstabilized). Mix, and dissolve the raloxifene hydrochloride. Shake the solution for approximately 30 min, followed by approximately 30 min of sonication. Let it stand at 30 for at least 6 h. Dilute with Diluent to 50.0 mL. [Note—Raloxifene hydrochloride is partly converted to raloxifene N-oxide under these conditions. The reaction time can be varied as necessary to achieve an appropriate level of raloxifene N-oxide. ]
for at least 6 h. Dilute with Diluent to 50.0 mL. [Note—Raloxifene hydrochloride is partly converted to raloxifene N-oxide under these conditions. The reaction time can be varied as necessary to achieve an appropriate level of raloxifene N-oxide. ]
System suitability solution:
Transfer 15 mg of USP Raloxifene Hydrochloride RS to a 50-mL volumetric flask, and add 5.0 mL of System suitability stock solution and 20 mL of Diluent. Dilute with Solution A to volume.
Standard stock solution:
0.06 mg/mL of USP Raloxifene Hydrochloride RS in Diluent
Standard solution:
Mix 5 mL of the Standard stock solution and 45 mL of Diluent, 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, and shake to disintegrate the Tablets. Sonicate, if necessary, and add Diluent 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
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 size:
10 µL
System suitability
Sample:
System suitability solution
Suitability requirements
Resolution:
NLT 3.0 between raloxifene and raloxifene N-oxide
Tailing factor:
NMT 2.0 for the raloxifene peak
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 Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of each impurity from the Sample solution |
| rS | = | = peak response of raloxifene from the Standard solution |
| CS | = | = concentration of USP Raloxifene Hydrochloride RS in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of the Sample solution (mg/mL) |
Acceptance criteria:
See Table 2.
Table 2
| Name | Relative Retention Time |
Acceptance Criteria, NMT (%) |
|---|---|---|
| Raloxifene | 1.00 | — |
| Raloxifene N-oxidea | 1.17 | 0.3 |
| Any unspecified individual impurity | — | 0.2 |
| Total impurities | — | 1.0 |
|
a
Methanone, [6-hydroxy-2-(4-hydroxyphenyl) benzo[b]thien-3-yl][4-[2-(1-oxido-1-piperidinyl)ethoxy]phenyl].
|
||
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in tight containers, and store at controlled room temperature.
• USP Reference Standards 11
11
USP Raloxifene Hydrochloride RS 
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Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Mary S. Waddell
Scientific Liaison 1-301-816-8124 |
(SM42010) Monographs - Small Molecules 4 |
| 711 |
Margareth R.C. Marques, Ph.D.
Senior Scientific Liaison 1-301-816-8106 |
(GCDF2010) General Chapters - Dosage Forms |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 4516
Pharmacopeial Forum: Volume No. 36(2) Page 427