Sorafenib 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

Sorafenib Tablets contain an amount of Sorafenib Tosylate equivalent to NLT 95.0% and NMT 105.0% of the labeled amount of sorafenib (C₂₁H₁₆ClF₃N₄O₃).

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

PROCEDURE

Solution A: 1 g/L of monobasic potassium phosphate in water. Adjust with phosphoric acid to a pH of 2.4. Solution B: Alcohol, absolute, acetonitrile, and Solution A (16:24:60)

Solution C: Alcohol, absolute and acetonitrile (40:60)

Solution D: Water. Adjust with phosphoric acid to a pH of 2.4.

Mobile phase: See Table 1. Return to original conditions and re-equilibrate the system.

Table 1

Diluent: Solution C and Solution D (75:25)

Standard solution: 0.22 mg/mL of USP Sorafenib Tosylate RS in Diluent. Sonicate to aid the dissolution. [NOTE—It is equivalent to 0.16 mg/mL of sorafenib in Diluent.]

Sample stock solution: Nominally equivalent to 4 mg/mL of sorafenib in Diluent, prepared as follows. Cut 5 Tablets into small pieces and transfer into a 250-mL volumetric flask. Add 150 mL of Diluent, shake for NLT 5 h until completely disintegrated and dispersed, and dilute with Diluent to volume. Sonicate for 30 min, and centrifuge a portion of this solution for 5 min or pass a portion of this solution through a polytetrafluoroethylene (PTFE) [or equivalent] filter of 0.45-µm pore size. Use the clear supernatant for the Sample solution preparation.

Sample solution: Nominally equivalent to 0.16 mg/mL of sorafenib in Diluent, from Sample stock solution

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 235 nm. For Identification B, use a diode array detector in the range of 190–400 nm.

Column: 4.6-mm × 10-cm; 3.5-µm packing L1

Column temperature: 40° Flow rate: 1.5 mL/min

Injection volume: 10 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: 0.8–2.0

Relative standard deviation: NMT 1.5%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of sorafenib (C₂₁H₁₆ClF₃N₄O₃) in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × (M_r1/M_r2) × 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

C_S = concentration of USP Sorafenib Tosylate RS in the Standard solution (mg/mL)

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

M_r1 = molecular weight of sorafenib, 464.83

M_r2 = molecular weight of sorafenib tosylate, 637.03

Acceptance criteria: 95.0%–105.0%

4 PERFORMANCE TESTS

Change to read:

DISSOLUTION 〈711〉

Test 1 (RB 1-Jun-2023)

Medium: 0.1 N hydrochloric acid containing 1% sodium lauryl sulfate; 900 mL Apparatus 2: 100 rpm

Time: 15 min

Determine the percentage of the labeled amount of sorafenib (C₂₁H₁₆ClF₃N₄O₃) dissolved by using one of the following procedures.

Chromatographic procedure

Buffer: 1.0 g/L of monobasic potassium phosphate in water. Adjust with phosphoric acid to a pH of 2.5.

Mobile phase: Acetonitrile and Buffer (45:55) for Column A, or acetonitrile and Buffer (50:50) for Column B Standard stock solution: 1.54 mg/mL of USP Sorafenib Tosylate RS in methanol

Standard solution: 0.3 mg/mL of USP Sorafenib Tosylate RS, prepared as follows. Transfer 20 mL of Standard stock solution into a 100- mL volumetric flask and dilute with Medium to volume. [NOTE—It is equivalent to 0.22 mg/mL of sorafenib.]

Sample solution: Pass a portion of the solution under test through a filter of 10-µm pore size.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.) Mode: LC

Detector: UV 266 nm Columns

Column A: 2-mm × 5-cm; 5-µm packing L1

Column B: 3-mm × 5-cm; 5-µm packing L1

Column temperature: 40°

Flow rate: 2.5 mL/min for Column A or 3.0 mL/min for Column B Injection volume: 5 µL

System suitability

Sample: Standard solution Suitability requirements

Tailing factor: 0.8–2.0

Relative standard deviation: NMT 1.5% Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of sorafenib (C₂₁H₁₆ClF₃N₄O₃) dissolved:

Result = (r_U/r_S) × (C_S/L) × V × (M_r1/M_r2) × 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

C_S = concentration of USP Sorafenib Tosylate RS in the Standard solution (mg/mL)

L = label claim (mg/Tablet)

V = volume of Medium, 900 mL

M_r1 = molecular weight of sorafenib, 464.83

M_r2 = molecular weight of sorafenib tosylate, 637.03

Spectrophotometric procedure

Standard solution: 0.3 mg/mL of USP Sorafenib Tosylate RS, prepared as follows. Transfer an amount of USP Sorafenib Tosylate RS into a suitable volumetric flask, add methanol equivalent to 2.5% of the final volume, and dilute with Medium to volume. [NOTE—It is equivalent to 0.22 mg/mL of sorafenib.]

Sample solution: Centrifuge portions of the solution under test or pass through a suitable glass fiber filter of 1-µm pore size.

Instrumental conditions

Mode: UV

Analytical wavelength: 280 nm

Cell path length: 1 mm

Blank: Medium Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of sorafenib (C₂₁H₁₆ClF₃N₄O₃) dissolved:

Result = (A_U/A_S) × (C_S/L) × V × (M_r1/M_r2) × 100

A_U = absorbance of the Sample solution

A_S = absorbance of the Standard solution

C_S = concentration of USP Sorafenib Tosylate RS in the Standard solution (mg/mL)

L = label claim (mg/Tablet)

V = volume of Medium, 900 mL

M_r1 = molecular weight of sorafenib, 464.83

M_r2 = molecular weight of sorafenib tosylate, 637.03

Tolerances: NLT 75% (Q ) of the labeled amount of sorafenib (C₂₁H₁₆ClF₃N₄O₃) is dissolved.

Test 3: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3.

Medium: 0.1 N hy drochloric acid in water containing 1% sodium dodecyl sulfate; 900 mL

Apparatus 2: 100 rpm, with stationary basket (see  〈711〉 , Figures 2b and 2c)

Time: 15 min

Buffer: Dissolve 0.77 g of ammonium acetate in 1 L of water. Adjust with 2% (v/v) glacial acetic acid in water to a pH of 6.2.

Solution A: Acetonitrile and water (90:10)

Mobile phase: Solution A and Buffer (65:35)

Standard stock solution: 0.76 mg/mL of USP Sorafenib Tosylate RS in Solution A. Sonicate to dissolve.

Standard solution: 0.3 mg/mL of USP Sorafenib Tosylate RS from Standard stock solution in Medium

Sample solution: Pass a portion of the solution under test through suitable filter of 0.45-µm pore size, discarding the first 4 mL of the filtrate.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 285 nm

Column: 4.6-mm × 15-cm; 5-µm packing L1

Column temperature: 45°

Flow rate: 1.5 mL/min

Injection volume: 10 µL

Run time: NLT 2 times the retention time of sorafenib

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 sorafenib (C₂₁H₁₆ClF₃N₄O₃) dissolved:

Result = (r_U/r_S) × C_S × V × (M_r1/M_r2) × (1/L) × 100

r_U = peak response of sorafenib from the Sample solution

r_S = peak response of sorafenib from the Standard solution

C_S = concentration of USP Sorafenib Tosylate RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL

M_r1 = molecular weight of sorafenib, 464.83

M_r2 = molecular weight of sorafenib tosylate, 637.03

L = label claim (mg/Tablet)

Tolerances: NLT 80% (Q ) of the labeled amount of sorafenib (C₂₁H₁₆ClF₃N₄O₃) is dissolved. (RB 1-Jun-2023)

UNIFORMITY OF DOSAGE UNITS 〈905〉: Meet the requirements

5 IMPURITIES

ORGANIC IMPURITIES

Mobile phase, Diluent, Sample solution, and Chromatographic system: Proceed as directed in the Assay. Standard stock solution: Use the Standard solution from the Assay.

Standard solution: 0.44 µg/mL of USP Sorafenib Tosylate RS in Diluent, from the Standard stock solution

System suitability solution: 0.44 µg/mL of USP Sorafenib Related Compound H RS in Standard stock solution Sensitivity solution: 0.22 µg/mL of USP Sorafenib Tosylate RS in Diluent, from the Standard solution

System suitability

Samples: System suitability solution and Sensitivity solution Suitability requirements

Resolution: NLT 1.5 between the sorafenib related compound H and sorafenib peaks, System suitability solution Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Samples: Sample solution and Standard solution Disregard the process impurity peaks listed in Table 2.

Table 2

^a 4-(4-Aminophenoxy)-N-methylpicolinamide.  

^b  It is the counter ion of sorafenib and is present in the chromatogram of the Sample solution.

^c  Ethyl (4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl)carbamate.

^d N,N’-Bis{4-[2-(N-methylcarbamoyl)-4-pyridyloxy]phenyl}urea.

^e Isopropyl {4-[2-(methylcarbamoyl)pyridin-4-yl]oxyphenyl}carbamate.

^f 4-Chloro-3-(trifluoromethyl)aniline.

^g N-Methyl-4-{4-[3-(3-trifluoromethylphenyl)ureido]phenoxy}picolinamide.

^h Ethyl [4-chloro-3-(trifluoromethyl)phenyl]carbamate.

ⁱ 1,3-Bis[4-chloro-3-(trifluoromethyl)phenyl]urea.

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

Result = (r_U/r_S) × (C_S/C_U) × (M_r1/M_r2) × 100

r_U = peak response of each impurity from the Sample solution

r_S = peak response of sorafenib from the Standard solution

C_S = concentration of USP Sorafenib Tosylate RS in the Standard solution (mg/mL)

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

M_r1 = molecular weight of sorafenib, 464.83

M_r2 = molecular weight of sorafenib tosylate, 637.03

Acceptance criteria: See Table 3. The reporting threshold is 0.1%.

Table 3

6 SPECIFIC TESTS

MICROBIAL ENUMERATION TESTS 〈61〉 and TESTS FOR SPECIFIED MICROORGANISMS 〈62〉: The total aerobic microbial count is NMT 103 cfu/g, and the total combined molds and yeasts count is NMT 102 cfu/g. It meets the requirements of the tests for the absence of Escherichia coli.

7 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight containers. Store at a temperature between 15° and 30° in a dry place. Add the following:

LABELING: When more than one Dissolution test is given, the labeling states the Dissolution test used only if Test 1 is not used. (RB 1-Jun-2023)

USP REFERENCE STANDARDS 〈11〉

USP Sorafenib Tosylate RS

USP Sorafenib Related Compound H RS

4-(4-{3-[2-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N-methylpicolinamide.

C₂₁H₁₆ClF₃N₄O₃          464.83