Tolcapone

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

C₁₄H₁₁NO₅ 273.24

Methanone, (3,4-dihydroxy-5-nitrophenyl)(4-methylphenyl)-;

3,4-Dihydroxy-4′-methyl-5-nitrobenzophenone CAS RN®: 134308-13-7; UNII: CIF6334OLY.

1 DEFINITION

Tolcapone contains NLT 98.5% and NMT 101.5% of tolcapone (C₁₄H₁₁NO₅), calculated on the anhydrous and solvent-free basis.

2 IDENTIFICATION

Change to read:

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

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

3.1 Procedure

Diluent: Methanol and acetonitrile (24:15)

Buffer: Transfer 6.8 g of monobasic potassium phosphate into a 1-L volumetric flask. Dissolve in about 980 mL of water. Adjust with phosphoric acid to a pH of 2.0. Dilute with water to volume.

Mobile phase: Acetonitrile, methanol, and Buffer (25:40:35)

System suitability stock solution: 5 µg/mL of USP Tolcapone Related Compound A RS, 5 µg/mL of USP Tolcapone RS, and 10 µg/mL of USP Tolcapone Related Compound B RS in Diluent

System suitability solution: 0.1 µg/mL of USP Tolcapone Related Compound A RS, 0.1 µg/mL of USP Tolcapone RS, and 0.2 µg/mL of USP Tolcapone Related Compound B RS from System suitability stock solution prepared as follows. Transfer a suitable volume of System suitability stock solution to a suitable volumetric flask. Add 63% of the flask volume of Diluent and dilute with water to volume.

Standard stock solution: 1.0 mg/mL of USP Tolcapone RS in Diluent

Standard solution: 0.1 mg/mL of USP Tolcapone RS from Standard stock solution prepared as follows. Transfer a suitable volume of Standard stock solution to a suitable volumetric flask. Add 55% of the flask volume of Diluent and dilute with water to volume.

Sample stock solution: 1.0 mg/mL of Tolcapone in Diluent

Sample solution: 0.1 mg/mL of Tolcapone from Sample stock solution prepared as follows. Transfer a suitable volume of Sample stock solution to a suitable volumetric flask. Add 55% of the flask volume of Diluent and dilute with water to volume.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 230 nm
• Column: 4.0-mm × 25-cm; 5-µm packing L1
• Flow rate: 1 mL/min
• Injection volume: 20 µL

System suitability

• Samples: System suitability solution and Standard solution
• [Note-The relative retention times are given in Table 1.]
• Suitability requirements
• Resolution: NLT 4.0 between tolcapone related compound B and tolcapone, System suitability solution
• Relative standard deviation: NMT 1.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of tolcapone (C₁₄H₁₁NO₅) in the portion of Tolcapone taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × 100

rᵤ = peak area from the Sample solution

rₛ = peak area from the Standard solution

Cₛ = concentration of USP Tolcapone RS in the Standard solution (mg/mL)

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

Acceptance criteria: 98.5%–101.5% on the anhydrous and solvent-free basis

4 IMPURITIES

4.1 Residue on Ignition 〈281〉

Acceptance criteria: NMT 0.1%

4.2 Organic Impurities

Diluent, Mobile phase, System suitability solution, Standard solution, Sample solution, Chromatographic system, and System suitability: Proceed as directed in the Assay.

Analysis

Samples: Standard solution and Sample solution

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

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × (1/F) × 100

rᵤ = peak area of any impurity from the Sample solution

rₛ = peak area of tolcapone from the Standard solution

Cₛ = concentration of USP Tolcapone RS in the Standard solution (mg/mL)

Cᵤ = concentration of Tolcapone in the Sample solution (mg/mL)

F = relative response factor of the impurity (see Table 1)

Acceptance criteria: See Table 1.

Table 1

5 SPECIFIC TESTS

Water Determination, Method I 〈921〉: NMT 0.1%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight, light-resistant containers.

USP Reference Standards 〈11〉

USP Tolcapone RS

USP Tolcapone Related Compound A RS

4′-Methyl-3,4-dihydroxybenzophenone C₁₄H₁₂O₃ 228.24

USP Tolcapone Related Compound B RS

4-Hydroxy-3-methoxy-4′-methyl-5-nitrobenzophenone C₁₅H₁₃NO₅ 287.27