Tolbutamide

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

C₁₂H₁₈N₂O₃S 270.35

Benzenesulfonamide, N-[(butylamino)carbonyl]-4-methyl-;

1-Butyl-3-(p-tolylsulfonyl)urea;

N-(Butylcarbamoyl)-4-methylbenzenesulfonamide CAS RN®: 64-77-7; UNII: 982XCM1FOI.

1 DEFINITION

Tolbutamide contains NLT 97.0% and NMT 103.0% of tolbutamide (C₁₂H₁₈N₂O₃S), calculated on the dried basis.

2 IDENTIFICATION

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

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

Buffer: 1.36 g/L of potassium phosphate, monobasic in water. Adjust with phosphoric acid to a pH of 3.5.

Mobile phase: Acetonitrile and Buffer (35:65)

Diluent: Acetonitrile and Buffer (70:30)

System suitability solution: 1 mg/mL of USP Tolbutamide RS and 10 µg/mL of USP Tolazamide RS in Diluent

Standard solution: 0.1 mg/mL of USP Tolbutamide RS in Diluent

Sample solution: 0.1 mg/mL of Tolbutamide in Diluent

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 230 nm
• Column: 4.6-mm × 25-cm; 5-µm packing L1
• Autosampler temperature: 4°
• Flow rate: 1.5 mL/min
• Injection volume: 30 µL
• Run time: NLT 1.5 times the retention time of tolbutamide

System suitability

• Samples: System suitability solution and Standard solution
• Suitability requirements
• Resolution: NLT 2.0 between tolbutamide and tolazamide, System suitability solution
• Tailing factor: NMT 2.0, Standard solution
• Relative standard deviation: NMT 0.73%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of tolbutamide (C₁₂H₁₈N₂O₃S) in the portion of Tolbutamide taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × 100

rᵤ = peak response of tolbutamide from the Sample solution

rₛ = peak response of tolbutamide from the Standard solution

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

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

Acceptance criteria: 97.0%–103.0% on the dried basis

4 IMPURITIES

Change to read:

4.1 Selenium 〈291〉, Procedures, Procedure 1

Sample: Mix 100 mg of tolbutamide with 100 mg of magnesium oxide.

Acceptance criteria: NMT 0.003%

4.2 Organic Impurities

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

Standard solution: 0.001 mg/mL of USP Tolbutamide RS in Diluent

Sensitivity solution: 0.5 µg/mL of USP Tolbutamide RS in Diluent from the Standard solution

Sample solution: 1 mg/mL of Tolbutamide in Diluent

System suitability

• Samples: System suitability solution, Standard solution, and Sensitivity solution
• Suitability requirements
• Resolution: NLT 2.0 between tolbutamide and tolazamide, System suitability solution
• Tailing factor: NMT 2.0, Standard solution
• Relative standard deviation: NMT 5.0%, Standard solution
• Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

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

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

rᵤ = peak response of each impurity from the Sample solution

rₛ = peak response of tolbutamide from the Standard solution

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

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

F = relative response factor (see Table 1)

Acceptance criteria: See Table 1. The reporting threshold is 0.05%.

Table 1

ᵃ N-Carbamoyl-4-methylbenzenesulfonamide.

ᵇ 4-Methylbenzenesulfonamide.

5 SPECIFIC TESTS

5.1 Loss on drying 〈731〉

Analysis: Dry at 105° for 3 h.

Acceptance criteria: NMT 0.5%

Sterility Tests 〈71〉: Where the label states that Tolbutamide is sterile, it meets the requirements.

Bacterial Endotoxins Test 〈85〉: Where the label states that Tolbutamide must be subjected to further processing during the preparation of injectable dosage forms, the levels of bacterial endotoxins are such that the requirement under the relevant dosage form monograph(s) in which Tolbutamide is used is met.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers.

Labeling: Where it is intended for use in preparing injectable dosage forms, the label states that it is sterile or must be subjected to further processing during the preparation of injectable dosage forms.

USP Reference standards 〈11〉

USP Tolazamide RS

USP Tolbutamide RS