Ketotifen Fumarate

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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C₁₉H₁₉NOS · C₄H₄O₄ 425.50

10H-Benzo[4,5]cyclohepta[1,2-b]thiophen-10-one, 4,9-dihydro-4-(1-methyl-4-piperidinylidene)-, (E)-2-butenedioate (1:1);

4,9-Dihydro-4-(1-methyl-4-piperidylidene)-10H-benzo[4,5]cyclohepta[1,2-b]thiophen-10-one fumarate (1:1);

4-(1-Methylpiperidin-4-ylidene)-4,9-dihydro-10H-benzo[4,5]cyclohepta[1,2-b]thiophen-10-one fumarate CAS RN®: 34580-14-8; UNII: HBD503WORO.

1 DEFINITION

Ketotifen Fumarate contains NLT 98.0% and NMT 102.0% of ketotifen fumarate (C₁₉H₁₉NOS · C₄H₄O₄ ), calculated on the dried basis.

2 IDENTIFICATION

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

Procedure

[Note—Protect solutions containing ketotifen fumarate from light.]

Solution A: 0.35 mL of triethylamine in 1 L of water

Solution B: 0.35 mL of triethylamine in 1 L of methanol

Mobile phase: See Table 1.

Table 1

Diluent: Methanol and water (50:50)

Standard solution: 0.3 mg/mL of USP Ketotifen Fumarate RS in Diluent

Sample solution: 0.3 mg/mL of Ketotifen Fumarate in Diluent

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 297 nm

Column: 4.0-mm × 15-cm; 3-μm packing L1

Column temperature: 40°

Flow rate: 1 mL/min

Injection volume: 20 μL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 0.73%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of ketotifen fumarate (C₁₉H₁₉NOS · C₄H₄O₄) in the portion of Ketotifen Fumarate taken:

Result = (r_U/r_S)x(C_S/C_U) × 100

r_U = peak response of ketotifen from the Sample solution

r_S = peak response of ketotifen from the Standard solution

C_S = concentration of USP Ketotifen Fumarate RS in the Standard solution (mg/mL)

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

Acceptance criteria: 98.0%–102.0% on the dried basis

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.1%

Organic Impurities

Solution A, Solution B, Mobile phase, Diluent, and Sample solution: Prepare as directed in the Assay.

System suitability solution: 0.3 mg/mL of USP Ketotifen Fumarate RS and 15 μg/mL of USP Ketotifen Related Compound G RS in Diluent

Sensitivity solution: 0.15 μg/mL of USP Ketotifen Fumarate RS in Diluent

Standard solution: 0.3 μg/mL each of USP Ketotifen Fumarate RS, USP Ketotifen Related Compound A RS, and USP Ketotifen Related

Compound G RS in Diluent

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 297 nm

Column: 4.0-mm × 15-cm; 3-μm packing L1

Column temperature: 40°

Flow rate: 1 mL/min

Injection volume: 30 μL

System suitability

Samples: System suitability solution, Sensitivity solution, and Standard solution

Suitability requirements

Resolution: NLT 1.5 between ketotifen and ketotifen related compound G, System suitability solution

Relative standard deviation: NMT 5.0% for ketotifen related compound G, ketotifen, and ketotifen related compound A, Standard solution

Signal-to-noise ratio: NLT 10 for ketotifen, Sensitivity solution

Analysis

Samples: Sample solution and Standard solution

Calculate the percentage of ketotifen related compound A and ketotifen related compound G in the portion of Ketotifen Fumarate taken:

Result = (r_U/r_S)x(C_S/C_U) × 100

r_U = peak response of ketotifen related compound A or ketotifen related compound G from the Sample solution

r_S = peak response of ketotifen related compound A or ketotifen related compound G from the Standard solution

C_S = concentration of USP Ketotifen Related Compound A RS or USP Ketotifen Related Compound G RS in the Standard solution (μg/mL)

C_U = concentration of Ketotifen Fumarate in the Sample solution (μg/mL)

Calculate the percentage of any unspecified impurity in the portion of Ketotifen Fumarate taken:

Result = (r_U/r_S)x(C_S/C_U ) × 100

r_U = peak response of any unspecified impurity from the Sample solution

r_S = peak response of ketotifen from the Standard solution

C_S = concentration of USP Ketotifen Fumarate RS in the Standard solution (μg/mL)

C_U = concentration of Ketotifen Fumarate in the Sample solution (μg/mL)

Acceptance criteria: See Table 2. The reporting threshold is 0.05%.

Table 2

5 SPECIFIC TESTS

Loss on Drying 〈731〉: NMT 0.5%

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

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers.

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

processing during the preparation of sterile dosage forms.

USP Reference Standards 〈11〉

USP Ketotifen Fumarate RS

USP Ketotifen Related Compound A RS

4-(4H-Benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)-1-methylpiperidine fumarate.

C₁₉H₁₉NOS · C₄H₄O₄ 409.50

USP Ketotifen Related Compound G RS

4-(1-Methylpiperidin-4-ylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophene-9,10-dione fumarate.

C₁₉H₁₇NO₂S · C₄H₄O₄ 439.48 (USP 1-Dec-2024)