Metoprolol 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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(C₁₅H₂₅NO₃)₂ · C₄H₄O₄             650.80

2-Propanol, 1-[4-(2-methoxyethyl)phenoxy]-3-[(1-methylethyl)amino]-, (±)-, (E)-2-butanedioate (2:1) (salt);

(+)-1-(Isopropylamino)-3-[p-(2-methoxyethyl)phenoxy]-2-propanol fumarate (2:1) (salt) CAS RN^®: 119637-66-0.

1 DEFINITION

Metoprolol Fumarate contains NLT 98.0% and NMT 102.0% of metoprolol fumarate [(C₁₅H₂₅NO₃)₂ · C₄H₄O₄], calculated on the dried basis. 

2 IDENTIFICATION

Change to read:

A. ^▲SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197K _{▲(CN 1-MAY-2020)}

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

Solution A: 1.3 g/L of sodium dodecyl sulfate in 0.1% (w/v) phosphoric acid

Solution B: Acetonitrile

Mobile phase: Solution A and Solution B (60:40)

Standard solution: 1 mg/mL of USP Metoprolol Fumarate RS in Mobile phase

Sample solution: 1 mg/mL of Metoprolol Fumarate in Mobile phase

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 223 nm

Column: 4.6-mm x 15-cm; 5-µm packing L7

Column temperature: 30°

Flow rate: 1 mL/min

Injection volume: 10 µL

Run time: 10 min

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2

Relative standard deviation: NMT 0.73%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of metoprolol fumarate [(C₁₅H₂₅NO₃)₂ · C₄H₄O₄] in the portion of Metoprolol Fumarate taken: 

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

r_U = peak response of metoprolol from the Sample solution

r_S = peak response of metoprolol from the Standard solution

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

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

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

4 IMPURITIES

4.1 RESIDUE ON IGNITION (281)

NMT 0.1%

4.2 ORGANIC IMPURITIES

Solution A: 1.3 g/L of sodium dodecyl sulfate in 0.1% (w/v) phosphoric acid

Solution B: Acetonitrile

Mobile phase: See Table 1.

Table 1

Diluent: Solution A and Solution B (60:40)

System suitability solution: 5 µg/mL each of USP Metoprolol Fumarate RS, USP Metoprolol Related Compound A RS, USP Metoprolol Related Compound B RS, and USP Metoprolol Related Compound C RS in Diluent

Standard solution: 2.5 µg/mL each of USP Metoprolol Fumarate RS, USP Metoprolol Related Compound A RS, USP Metoprolol Related Compound B RS, USP Metoprolol Compound C RS, and USP Metoprolol Related Compound D. RS in Diluent

Sample solution: 1 mg/mL of Metoprolol Fumarate in Diluent

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 223 nm

Column: 4.6-mm x 15-cm; 5-µm packing L7

Column temperature: 30°

Flow rate: 1 mL/min

Injection volume: 10 µL

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 1.5 between metoprolol related compound A and metoprolol related compound B; NLT 2.5 between metoprolol related compound B and metoprolol related compound C, System suitability solution

Relative standard deviation: NMT 2.0% for metoprolol, metoprolol related compound A, metoprolol related compound B, metoprolol related compound C, and metoprolol related compound D, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the corresponding metoprolol related compound in the portion of Metoprolol Fumarate taken:

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

r_U = peak response of the corresponding metoprolol related compound in the Sample solution

r_S = peak response of the corresponding metoprolol related compound in the Standard solution

C_S = concentration of the corresponding USP Metoprolol Related Compound RS in the Standard solution (µg/mL)

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

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

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

r_U = peak response of each unspecified impurity in the Sample solution

r_S = peak response of metoprolol in the Standard solution S

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

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

Acceptance criteria: See Table 2. Disregard peaks below 0.03%.

Table 2

^a 4-[2-Hydroxy-3-(isopropylamino)propoxy] benzaldehyde hydrochloride.

^b1-Chloro-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol.

^c 1-Ethylamino-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol.

^d N,N-Bis(2-hydroxy-3-[4-(2-methoxyethyl)phenoxy]propyl}isopropylamine hydrochloride.

5 SPECIFIC TESTS

5.1 PH (791)

5.5-6.5, in a solution (1 in 10)

5.2 LOSS ON DRYING (731)

Analysis: Dry under vacuum at 60° for 4 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight, light-resistant containers. Store at controlled room temperature.

USP REFERENCE STANDARDS (11)

USP Metoprolol Fumarate RS

USP Metoprolol Related Compound A RS

1-Ethylamino-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol.

C₁₄H₂₃NO3              253.34

USP Metoprolol Related Compound B.RS

1-Chloro-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol.

C₁₂H1₇CIO₃            244.71

USP Metoprolol Related Compound C RS

4-[2-Hydroxy-3-(isopropylamino) propoxy]benzaldehyde hydrochloride.

C₁₃H₁₉NO₃ · HCI        273.76

USP Metoprolol Related Compound D RS

N,N-Bis(2-hydroxy-3-[4-(2-methoxyethyl)phenoxy]propyl}isopropylamine hydrochloride.

C₂₇H₄₁NO₆ · HCI        512.08