Formoterol 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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(C₁₉H₂₄N₂O₄)₂ · C₄H₄O₄ · 2H₂O 840.92

Formamide, N-[2-hydroxy-5-[1-hydroxy-2-[[1-(4-methoxyphenyl)propan-2-yl]amino] ethyl]phenyl], (R*,R*)-, fumarate (2:1) (salt), dihydrate;

(±)-2′-Hydroxy-5′-[(R*)-1-hydroxy-2-[[(R*)-p-methoxy-α-methylphenethyl] amino] ethyl] formanilide fumarate (2:1) (salt), dihydrate CAS RN®: 183814-30-4; UNII: W34SHF8J2K.

Anhydrous

(C₁₉H₂₄N₂O₄)₂ · C₄H₄O₄ 804.89 CAS RN®: 43229-80-7.

1 DEFINITION

Formoterol Fumarate contains NLT 98.5% and NMT 101.5% of formoterol fumarate [(C₁₉H₂₄N₂O₄)₂ · C₄H₄O₄], calculated on the anhydrous basis.

2 IDENTIFICATION

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

B. The retention time of the formoterol peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

3 ASSAY

3.1 Procedure

Protect solutions of formoterol fumarate from light.

Buffer: 6.1 g/L of monobasic sodium phosphate and 1.0 g/L of dibasic sodium phosphate dihydrate in water. [Note - The pH is 6.0 ± 0.1.]

Solution A: 3.7 g/L of monobasic sodium phosphate and 0.35 g/L of phosphoric acid in water. [Note - The pH is 3.1 ± 0.1.]

Solution B: Acetonitrile

Mobile phase: See Table 1.

Table 1

Diluent: Acetonitrile and Buffer (16:84)

Standard solution: 0.2 mg/mL of USP Formoterol Fumarate RS in Diluent

Sample solution: 0.2 mg/mL of Formoterol Fumarate in Diluent

3.2 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 214 nm

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

Flow rate: 1 mL/min

Injection volume: 10 μL

3.3 System suitability

Sample: Standard solution

3.4 Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 0.73%

3.5 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of formoterol fumarate [(C₁₉H₂₄N₂O₄)₂ · C₄H₄O₄] in the portion of Formoterol Fumarate taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of formoterol from the Sample solution

r_S = peak response of formoterol from the Standard solution

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

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

Acceptance criteria: 98.5%–101.5% on the anhydrous basis

4 IMPURITIES

4.1 Residue on Ignition

Sample: 1 g

Acceptance criteria: NMT 0.1%

Change to read:

4.2 Organic Impurities

Protect solutions of formoterol fumarate from light.

Buffer, Solution A, Solution B, and Diluent: Prepare as directed in the Assay.

Mobile phase: See Table 2.

Table 2

System suitability solution: 0.2 mg/mL of USP Formoterol Fumarate RS and 2 μg/mL each of USP Formoterol Related Compound A RS, USP Formoterol Related Compound C RS, and USP Formoterol Related Compound D RS in Diluent. Sonicate to dissolve prior to final dilution.

Sensitivity solution: 0.1 μg/mL of USP Formoterol Fumarate RS in Diluent

Sample solution: 0.2 mg/mL of Formoterol Fumarate in Diluent. Sonicate to dissolve before final dilution.

4.2.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 214 nm

Column: 4.6-mm × 15-cm; packing L7

Flow rate: 1 mL/min

Injection volume: 20 μL

4.2.2 System suitability

Samples: System suitability solution and Sensitivity solution

[Note - The relative retention times for the peaks are given in Table 3.]

4.2.3 Suitability requirements

Resolution: NLT 2.0 between formoterol and formoterol related compound C; and NLT 1.2 (USP 1-May-2022) between formoterol related compound C and formoterol related compound D, System suitability solution

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

4.2.4 Analysis

Sample: Sample solution

Calculate the percentage of each impurity in the portion of Formoterol Fumarate taken:

Result = (r_U/r_T) × (1/F) × 100

r_U = peak response of each impurity from the Sample solution

r_T= sum of the responses of all peaks from the Sample solution

F = relative response factor for each peak (see Table 3)

Acceptance criteria: See Table 3. The reporting threshold is 0.05%.

Table 3

^a Salt counter ion included for identification only, not to be reported or included in the total impurities.

^b 1-(4-Methoxyphenyl)propan-2-amine.

^c N-(2-Hydroxy-5-{1-hydroxy-2-[(4-methoxyphenethyl) amino]ethyl}phenyl) formamide.

^d N-[2-Hydroxy-5-(1-hydroxy-2-{[1-(4-methoxy-3-methylphenyl)propan-2-yl]amino} ethyl)phenyl]formamide.

^e N-[2-Hydroxy-5-(1-{[2-hydroxy-5-(1-hydroxy-2-{[1-(4-methoxyphenyl)propan-2-yl]amino}ethyl)phenyl]amino}-2-{[1-(4-methoxyphenyl)propan-2-yl]amino}ethyl)phenyl]formamide.

^f When present in the chromatogram, the formoterol dimer diasteromers will appear as multiple overlapped peaks, for which the total peak area is to be assessed.

^g N-{5-[(RS)-2-{Benzyl[(RS)-1-(4-methoxyphenyl)propan-2-yl]amino}-1-hydroxyethyl]-2-hydroxyphenyl}formamide.

Change to read:

4.3 Limit of Formoterol Related Compound I

Buffer: 4.2 g/L of tribasic potassium phosphate. Adjust with potassium hydroxide or phosphoric acid to a pH of 12.0 ± 0.1.

Mobile phase: Acetonitrile and Buffer (12:88)

System suitability solution: 100 μg/mL of USP Formoterol Fumarate RS and 1 μg/mL of USP Formoterol Related Compound I RS (USP 1- May-2022) in water

Standard solution: 0.3 μg/mL of USP Formoterol Fumarate RS in water (USP 1-May-2022)

Sample solution: 100 μg/mL (USP 1-May-2022) of Formoterol Fumarate in water (USP 1-May-2022)

4.3.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 225 nm

Column: 4.6-mm × 15-cm; 5-μm (USP 1-May-2022) packing L67

Flow rate: 0.5 mL/min

Injection volume: 20 μL

Run time: NLT 2 times the retention time of formoterol

4.3.2 System suitability

Samples: System suitability solution and Standard solution (USP 1-May-2022)

[Note - The relative retention times for formoterol and formoterol related compound I are 1.0 and 1.17, respectively.]

4.3.3 Suitability requirements

Peak-to-valley ratio: NLT 2.5 for formoterol related compound I and formoterol, System suitability solution

Relative standard deviation: NMT 5.0%, Standard solution (USP 1-May-2022)

4.3.4 Analysis

Samples: Standard solution and (USP 1-May-2022) Sample solution

Calculate the percentage of formoterol related compound I in the portion of Formoterol Fumarate taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of formoterol related compound I from the Sample solution

r_S = peak response of formoterol from the Standard solution

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

C_U = concentration of Formoterol Fumarate in the Sample solution (μg/mL) (USP 1-May-2022)

Acceptance criteria: NMT 0.3% (USP 1-May-2022)

5 SPECIFIC TESTS

pH 〈791〉

Sample solution: 1 mg/mL in water

Acceptance criteria: 5.5–6.5

Water Determination 〈921〉, Method I: 4.0%–5.0%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed light-resistant containers.

Change to read:

USP Reference Standards 〈11〉

USP Formoterol Fumarate RS (USP 1-May-2022)

USP Formoterol Related Compound A RS

2-Amino-4-(1-hydroxy-2-((1-(4-methoxyphenyl)propan-2-yl)amino)ethyl)phenol.

C₁₈H₂₄N₂O₃ 316.40 (USP 1-May-2022)

USP Formoterol Related Compound C RS

N-(2-Hydroxy-5-(1-hydroxy-2-{[1-(4-methoxyphenyl)propan-2-yl]amino}ethyl)phenyl)acetamide fumarate (2:1) salt.

(C₂₀H₂₆N₂O₄)₂ · C₄H₄O₄ 832.95

USP Formoterol Related Compound D RS

N-(2-Hydroxy-5-(1-hydroxy-2-{[1-(4-methoxyphenyl)propan-2-yl](methyl)amino} ethyl)phenyl) formamide fumarate (2:1) salt.

(C₂₀H₂₆N₂O₄)₂ · C₄H₄O₄ 832.95

USP Formoterol Related Compound I RS

N-(2-Hydroxy-5-[(RS)-1-hydroxy-2-{[(SR)-1-(4-methoxyphenyl)propan-2-yl]amino} ethyl]phenyl)formamide.

C₁₉H₂₄N₂O₄ 344.41 (USP 1-May-2022)